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Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a high-mortality disease caused by multiple disorders such as COVID-19, influenza, and sepsis. Current therapies mainly rely on the inhalation of nitric oxide or injection of pharmaceutical drugs (e.g., glucocorticoids); however, their toxicity, side effects, or administration routes limit their clinical application. In this study, pachypodol (Pac), a hydrophobic flavonol with anti-inflammatory effects, was extracted from Pogostemon cablin Benth and intercalated in liposomes (Pac@liposome, Pac-lipo) to improve its solubility, biodistribution, and bioavailability, aiming at enhanced ALI/ARDS therapy. Nanosized Pac-lipo was confirmed to have stable physical properties, good biodistribution, and reliable biocompatibility. In vitro tests proved that Pac-lipo has anti-inflammatory property and protective effects on endothelial and epithelial barriers in lipopolysaccharide (LPS)-induced macrophages and endothelial cells, respectively. Further, the roles of Pac-lipo were validated on treating LPS-induced ALI in mice. Pac-lipo showed better effects than did Pac alone on relieving ALI phenotypes: It significantly attenuated lung index, improved pulmonary functions, inhibited cytokine expression such as TNF-α, IL-6, IL-1β, and iNOS in lung tissues, alleviated lung injury shown by HE staining, reduced protein content and total cell number in bronchoalveolar lavage fluid, and repaired lung epithelial and vascular endothelial barriers. As regards the underlying mechanisms, RNA sequencing results showed that the effects of the drugs were associated with numerous immune- and inflammation-related signaling pathways. Molecular docking and western blotting demonstrated that Pac-lipo inhibited the activation of the TLR4-MyD88-NF-κB/MAPK signaling pathway. Taken together, for the first time, our new drug (Pac-lipo) ameliorates ALI via inhibition of TLR4-MyD88-NF-κB/MAPK pathway-mediated inflammation and disruption of lung barrier. These findings may provide a promising strategy for ALI treatment in the clinic. [Display omitted] [ABSTRACT FROM AUTHOR]

Androgenetic alopecia (AGA) is a non-fatal disease prevalent worldwide. However, mixed efficacy has been observed among different therapies for hair regrowth in AGA patients. Thus, a nano-platform with synergistic treatments based on a hybrid extracellular vesicle encapsulating gold nanoparticles (AuNPs) and finasteride (Hybrid/Au@Fi) was constructed through membrane fusion between hair follicle stem cell (HFSC)-derived extracellular vesicles and liposomes. These hybrid vesicles (HVs) not only fuel hair regrowth by providing cellular signals in extracellular vesicles, but also improve storage stability, follicle retention, and drug encapsulation efficiency (EE%) for finasteride inhibiting 5α-reductase, and nano-size AuNPs that simulate low-level laser therapy (LLLT) with similar photothermal effects in vitro. The EE% of finasteride in these HVs reached 45.33%. The dual administration of these extracellular vesicles and finasteride showed a strong synergistic effect on HFSCs in vitro. In an AGA mouse model, once-daily topical Hybrid/Au@Fi (115.07 ± 0.32 nm, −7.50 ± 1.68 mV) gel led to a faster transition of hair follicles (HFs) from the catagen to the anagen, increased hair regrowth coverage, and higher quality of regrowth hair, compared to once-daily 5% minoxidil treatment. Compared to topical minoxidil, the multifaceted synergistic therapy of Hybrid/Au@Fi through topical administration offers a new option for intractable AGA patients with low side effects. [Display omitted] • These hybrid vesicles improved storage stability for cargos, follicle retention, and drug encapsulation efficiency (EE%) for finasteride. • The Hybrid/Au@Fi (115.07 ± 0.32 nm, −7.50 ± 1.68 mV) facilitated simulated in vitro layered dermal papilla cell (DPC) migration and angiogenesis with favorable cell dynamic behavior and no cytotoxicity. • In an AGA mouse model, once-daily topical application of Hybrid/Au@Fi gel exhibited a faster transition of hair follicles from the catagen to the anagen, higher hair regrowth coverage, and improved quality of regrowth hair, compared to once-daily 5% minoxidil treatment. [ABSTRACT FROM AUTHOR]

Multiple oxaliplatin-resistance mechanisms have been proposed such as increase of anti-inflammatory M2 macrophages and lack of cytotoxic T-cells. Thereby oxaliplatin chemotherapy promotes an immunosuppressive tumor microenvironment and inhibits anti-tumor efficacy. It has been shown that toll-like receptor (TLR) agonists are capable of triggering broad inflammatory responses, which may potentially reduce oxaliplatin-resistance and improve the efficacy of chemotherapy. In this study, we established colorectal tumor-bearing zebrafish and mice, and investigated the effects of TLR agonists and oxaliplatin in macrophage function and anti-tumor T cell immunity as well as tumor growth control in vivo. To increase the potential of this strategy as well minimize side effects, neutral liposomes carrying oxaliplatin and cationic liposomes co -loaded with TLR agonists Poly I:C and R848 were employed for maximum immune activation. Both of two liposomal systems exhibited good physicochemical properties and excellent biological activities in vitro. The combination strategy delivered by liposomes showed more pronounced tumor regression and correlated with decreased M2 macrophage numbers in both zebrafish and mice. Increasing numbers of dendritic cells, DC maturation and T cell infiltration mediated via immunogenic cell death were observed in treated mice. Our study offers valuable insights into the potential of liposomal combination therapy to improve cancer treatment by reprogramming the tumor microenvironment and enhancing immune responses. [Display omitted] [ABSTRACT FROM AUTHOR]

Brain-targeted drug delivery poses a great challenge due to the blood-brain barrier (BBB). In a previous study, we have developed a peptide-modified stealth liposome (SP-sLip) to enhance BBB penetration via the adsorption of apolipoproteins in plasma. SP is an 11-amino acid peptide derived from 25 to 35 of the Amyloid β peptide (Aβ 1–42), which is a nature ligand of apolipoproteins. Although freshly prepared SP-sLip exhibited efficient brain targeting performance, it occured self-aggregation and instability in storage. In this study, we developed a D-peptide ligand according to the reverse sequence of SP with D-amino acids, known as DSP, to improve the stability in storage. Notably, DSP exhibited a reduced tendency for self-aggregation and improved stability in comparison to the SP peptide. Furthermore, compared to SP-sLip, DSP-modified sLip (DSP-sLip) demonstrated enhanced stability (>2 weeks), prolonged blood circulation (AUC increased 44.4%), reduced liver and spleen accumulation (reduced by 2.23 times and 1.86 times) with comparable brain-targeting efficiency. Similar to SP-sLip, DSP-sLip selectively adsorbed apolipoprotein A1, E, and J in the blood to form functionalized protein corona, thus crossing BBB via apolipoprotein receptor-mediated transcytosis. These findings underscored the importance of ligand stability in the in vitro and in vivo performance of brain-targeted liposomes, therefore paving the way for the design and optimization of efficient and stable nanocarriers. DSP-sLip maintained the brain-targeted ability of SP-sLip by selectively adsorbing apolipoproteins in blood and crossing BBB via apolipoprotein receptors. Compared to SP-sLip, DSP-sLip exhibited less aggregation in storage, enhanced stability, extended blood circulation, and reduced liver/spleen accumulation in vivo [Display omitted] • DSP-sLip exhibited less self-aggregation and enhanced stability in storage compared to SP-sLip. • DSP-sLip maintained ability to absorb apolipoproteins in blood to form functionalized protein corona. • DSP-sLip had enhanced stability, prolonged circulation, reduced liver accumulation with comparable brain-targeting efficiency as SP-sLip. [ABSTRACT FROM AUTHOR]

Peritoneal carcinomatosis (PC) is characterized by a high recurrence rate and mortality following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC), primarily due to incomplete cancer elimination. To enhance the standard of care for PC, we developed two cationic liposomal formulations aimed at localizing a toll-like receptor agonist, resiquimod (R848), in the peritoneal cavity to activate the immune system locally to specifically eradicate residual tumor cells. These formulations effectively extended R848 retention in the peritoneum by >10-fold, resulting in up to a 2-fold increase in interferon α (IFN-α) induction in the peritoneal fluid, without increasing the plasma levels. In a CT26 colon cancer model with peritoneal metastases, these liposomal R848 formulations, when combined with oxaliplatin (OXA)—an agent used in HIPEC that induces immunogenic cell death—increased tumor infiltration of effector immune cells, including DCs, CD4, and CD8 T cells. This led to the complete elimination of PC in 60–70% of the mice, while the control mice reached humane endpoints by 30 days. The cured mice developed specific antitumor immunity, as re-challenging them with the same tumor cells did not result in tumor establishment. However, inoculation with a different tumor line led to tumor development. Additionally, exposing CT26 tumor antigens to the splenocytes isolated from the cured mice induced the expansion of CD4 and CD8 T cells and the release of IFN-γ, demonstrating long-term immune memory to the specific tumor. The anti-tumor efficacy of these liposomal R848 formulations was mediated via CD8 T cells with different levels of involvement of CD4 and B cells, and the combination with an anti-PD-1 antibody achieved a cure rate of 90%. [Display omitted] • Cationic liposomes loaded with resiquimod extended retention in the peritoneum. • Resiquimod-loaded liposomes with oxaliplatin eradicated PC in 60–70% of mice. • Cured mice developed long-term, specific anti-tumor immunity. • In combination with anti-PD-1therapy, the treatment achieved a 90% cure rate in mice. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a high mortality rate due to limited treatment options. Current therapies cannot effectively reverse the damage caused by IPF. Research suggests that promoting programmed cell death (apoptosis) in myofibroblasts, the key cells driving fibrosis, could be a promising strategy. However, inducing apoptosis in healthy cells like epithelial and endothelial cells can cause unwanted side effects. This project addresses this challenge by developing a targeted approach to induce apoptosis specifically in myofibroblasts. We designed liposomes (LPS) decorated with peptides that recognize VCAM-1, a protein highly expressed on myofibroblasts in fibrotic lungs. These VCAM1-targeted LPS encapsulate Venetoclax (VNT), a small molecule drug that inhibits BCL-2, an anti-apoptotic protein. By delivering VNT directly to myofibroblasts, we hypothesize that VCAM1-VNT-LPS can selectively induce apoptosis in these cells, leading to reduced fibrosis and improved lung function. We successfully characterized VCAM1-VNT-LPS for size, surface charge, and drug loading efficiency. Additionally, we evaluated their stability over three months at different temperatures. In vitro and in vivo studies using a bleomycin-induced mouse model of lung fibrosis demonstrated the therapeutic potential of VCAM1-VNT-LPS. These studies showed a reduction in fibrosis-associated proteins (collagen, α-SMA, VCAM1) and BCL-2, while simultaneously increasing apoptosis in myofibroblasts. These findings suggest that VCAM1-targeted delivery of BCL-2 inhibitors using liposomes presents a promising and potentially selective therapeutic approach for IPF. [Display omitted] • Targeting apoptosis in myofibroblasts may offer a novel therapeutic approach for fibrosis treatment. • VCAM1-VNT-LPS, a VCAM1-targeted liposome loaded with a BCL-2 inhibitor, effectively reduced fibrosis in a preclinical model. • This approach holds promise for developing a new and effective treatment for pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Liposomes are widely used as drug delivery nanoplatforms because of their versatility and biocompatibility; however, their ability to load certain drugs may be suboptimal. In this study, we generated liposomes using a combination of DSPE and DSPE-PEG-2 k lipids and loaded them with doxorubicin (DOX) and paclitaxel (PTX), to investigate the effects of light emitting diode (LED) irradiation on liposome structure and drug loading efficiency. Scanning and transmission electron microscopy revealed that the surface of liposomes irradiated with blue or near-infrared LEDs (LsLipo) was rougher and more irregular than that of non-LED-irradiated liposomes (NsLipo). Nuclear magnetic resonance analysis showed that the hydrogen peak originating from the lipid head groups was lower in LsLipo than in NsLipo preparations, indicating that LED irradiation changed the chemical and physical properties of the liposome. Structural changes, such as reduced rigidity, induced by LED irradiation, increased the loading efficiency of DOX and PTX. In vitro and in vivo experiments showed that LsLipo were more effective at inhibiting the growth of cancer cells than NsLipo. Our findings suggest that LED irradiation enhances the drug delivery efficacy of liposomes and offer new possibilities for improving drug delivery systems. [Display omitted] [ABSTRACT FROM AUTHOR]

Cholesterol is an indispensable component of most liposomes, heavily influencing their physical and surface properties. In this study, cholesterol in non-PEGylated liposomes was replaced by its analog, asiatic acid (AA), to generate liposomes with an alternative composition. These AA liposomes are generally smaller and more rigid than conventional liposomes, circulate longer in the body, and accumulate more in primary tumors and lung metastases in vivo. On the other hand, as an active ingredient, AA can decrease TGF-β secretion to inhibit the epithelial-mesenchymal transition (EMT) process, increase the sensitivity of tumor cells to doxorubicin (DOX), and synergize with DOX to enhance the immune response, thus improving their antitumor and anti-metastasis efficiency. Based on this rationale, DOX-loaded AA liposomes were fabricated and tested against triple-negative breast cancer (TNBC). Results showed that compared with conventional liposomes, the DOX-AALip provided approximately 28.4% higher tumor volume reduction with almost no metastatic nodules in the mouse model. Our data demonstrate that AA liposomes are safe, simple, and efficient, and thus in many situations may be used instead of conventional liposomes, having good potential for further clinical translational development. (A) Structure of AA and cholesterol. (B) Schematic diagram of the preparation process of DOX-Lip and DOX-AALip. (C) Schematic illustration of the suppression of tumor development and metastasis by DOX-AALip in a TNBC mouse model [Display omitted] • Asiatic acid (AA) may both work as a cholesterol replacement and as an anti-tumor agent. • These AA liposomescould achieve simultaneous targeting of primary tumors and metastatic lesions. • DOX-AALip is prepared in the same way as conventional liposomes. [ABSTRACT FROM AUTHOR]

Poly-ethylene-glycol (PEG)-based nanoparticles (NPs) - including cylindrical micelles (CNPs), spherical micelles (SNPs), and PEGylated liposomes (PLs) - are hypothesized to be cleared in vivo by opsonization followed by liver macrophage phagocytosis. This hypothesis has been used to explain the rapid and significant localization of NPs to the liver after administration into the mammalian vasculature. Here, we show that the opsonization-phagocytosis nexus is not the major factor driving PEG-NP – macrophage interactions. First, mouse and human blood proteins had insignificant affinity for PEG-NPs. Second, PEG-NPs bound macrophages in the absence of serum proteins. Third, lipoproteins blocked PEG-NP binding to macrophages. Because of these findings, we tested the postulate that PEG-NPs bind (apo)lipoprotein receptors. Indeed, PEG-NPs triggered an in vitro macrophage transcription program that was similar to that triggered by lipoproteins and different from that triggered by lipopolysaccharide (LPS) and group A Streptococcus. Unlike LPS and pathogens, PLs did not increase transcripts involved in phagocytosis or inflammation. High-density lipoprotein (HDL) and SNPs triggered remarkably similar mouse bone-marrow-derived macrophage transcription programs. Unlike opsonized pathogens, CNPs, SNPs, and PLs lowered macrophage autophagosome levels and either reduced or did not increase the secretion of key macrophage pro-inflammatory cytokines and chemokines. Thus, the sequential opsonization and phagocytosis process is likely a minor aspect of PEG-NP – macrophage interactions. Instead, PEG-NP interactions with (apo)lipoprotein and scavenger receptors appear to be a strong driving force for PEG-NP – macrophage binding, entry, and downstream effects. We hypothesize that the high presence of these receptors on liver macrophages and on liver sinusoidal endothelial cells is the reason PEG-NPs localize rapidly and strongly to the liver. [Display omitted] [ABSTRACT FROM AUTHOR]

Gemcitabine (GEM) is a non-selective chemotherapeutic agent used in the treatment of pancreatic cancer. Its antitumor efficacy is limited by a short plasma half-life and severe adverse reactions. To overcome these shortcomings, four novel lipid-like GEM diesters were synthesized and encapsulated into liposomes. Through optimization, dimyristoyl GEM (dmGEM)-loaded liposomes (LipodmGEM) were successfully obtained with an almost complete encapsulation efficiency. Compared to free GEM, LipodmGEM showed enhanced cellular uptake and cell apoptosis, improved inhibition of cell migration on AsPC-1 cells and a greatly extended half-life (7.22 vs. 1.78 h). LipodmGEM succeeded in enriching the drug in the tumor (5.28 vs. 0.03 μmol/g at 8 h), overcoming a major shortcoming of GEM, showed excellent anticancer efficacy in vivo and negligible systemic toxicity, superior to GEM. Attractive as well, suspensions of LipodmGEM remained stable at 2–10 °C away from light for no <2 years. Our results suggest that LipodmGEM might become of high interest for treating pancreatic cancer while the simple strategy we reported might be explored as well for converting other antitumor drugs with high water-solubility and short plasma half-life into attractive nanomedicines. [Display omitted] • A novel lipid-like gemcitabine diester was synthesized and encapsulated into liposome (LipodmGEM). • LipodmGEM remained stable at 2–10 °C for no less than 2 years. • LipodmGEM greatly extended the half-life and enriched in tumor. • LipodmGEM significantly improved antitumor efficacy and reduced systemic toxicity. • LipodmGEM showed outstanding tumor metastasis inhibition ability. [ABSTRACT FROM AUTHOR]

Herpes simplex keratitis (HSK) is a common blinding corneal disease caused by herpes simplex virus type 1 (HSV-1) infection. Antiviral drugs and corticosteroids haven't shown adequate therapeutic efficacy. During the early stage of HSV-1 infection, macrophages serve as the first line of defense. In particular, CD169+ macrophages play an important role in phagocytosis and antigen presentation. Therefore, we constructed GM-gD-lip, a ganglioside GM1 liposome vaccine encapsulating HSV-1 glycoprotein D and targeting CD169+ macrophages. After subconjunctival injection of the vaccine, we evaluated the survival rate and ocular surface lesions of the HSK mice, as well as the virus levels in the tear fluid, corneas, and trigeminal ganglia. We discovered that GM-gD-lip reduced HSV-1 viral load and alleviated the clinical severity of HSK. The GM-gD-lip also increased the number of corneal infiltrating macrophages, especially CD169+ macrophages, and polarized them toward M1. Furthermore, the number of dendritic cells (DCs) and CD8+ T cells in the ocular draining lymph nodes was significantly increased. These findings demonstrated that GM-gD-lip polarized CD169+ macrophages toward M1 to eliminate the virus while cross-presenting antigens to CD8+ T cells via DCs to activate adaptive immunity, ultimately attenuating the severity of HSK. The use of GM-gD-lip as an immunotherapeutic method for the treatment of HSK has significant implications. [Display omitted] • Ganglioside GM1 liposome vaccine can target CD169+ macrophages. • Ganglioside GM1 liposome vaccine alleviated HSK and inhibited the replication of HSV-1. • Ganglioside GM1 liposome vaccine polarized CD169+ macrophages toward M1 and activated CD8+ T cell-mediated adaptive immunity. • Ganglioside GM1 liposome vaccine provided faster but incomplete immune protection for mice from HSK [ABSTRACT FROM AUTHOR]

Despite tremendous global efforts since the beginning of the COVID-19 pandemic, still only a limited number of prophylactic and therapeutic options are available. Although vaccination is the most effective measure in preventing morbidity and mortality, there is a need for safe and effective post-infection treatment medication. In this study, we explored a pipeline of 21 potential candidates, examined in the Calu-3 cell line for their antiviral efficacy, for drug repurposing. Ralimetinib and nafamostat, clinically used drugs, have emerged as attractive candidates. Due to the inherent limitations of the selected drugs, we formulated targeted liposomes suitable for both systemic and intranasal administration. Non-targeted and targeted nafamostat liposomes (LipNaf) decorated with an Apolipoprotein B peptide (ApoB-P) as a specific lung-targeting ligand were successfully developed. The developed liposomal formulations of nafamostat were found to possess favorable physicochemical properties including nano size (119–147 nm), long-term stability of the normally rapidly degrading compound in aqueous solution, negligible leakage from the liposomes upon storage, and a neutral surface charge with low polydispersity index (PDI). Both nafamostat and ralimetinib liposomes showed good cellular uptake and lack of cytotoxicity, and non-targeted LipNaf demonstrated enhanced accumulation in the lungs following intranasal (IN) administration in non-infected mice. LipNaf retained its anti-SARS-CoV 2 activity in Calu 3 cells with only a modest decrease, exhibiting complete inhibition at concentrations >100 nM. IN, but not intraperitoneal (IP) treatment with targeted LipNaf resulted in a trend to reduced viral load in the lungs of K18-hACE2 mice compared to targeted empty Lip. Nevertheless, upon removal of outlier data, a statistically significant 1.9-fold reduction in viral load was achieved. This observation further highlights the importance of a targeted delivery into the respiratory tract. In summary, we were able to demonstrate a proof-of-concept of drug repurposing by liposomal formulations with anti-SARS-CoV-2 activity. The biodistribution and bioactivity studies with LipNaf suggest an IN or inhalation route of administration for optimal therapeutic efficacy. [Display omitted] • Drug repurposing for COVID-19 therapy: Liposomal delivery of ralimetinib/nafamostat. • Inhibition of different SARS-CoV-2 variants including omicron. • Liposomal delivery system suitable for both systemic and intranasal administration. • Apo-B peptide decorated liposomes: Targeted delivery to proteoglycans and LDLr. • Marked virus inhibition in SARS-CoV-2 infected mice, without side effects. [ABSTRACT FROM AUTHOR]

Cerenkov radiation induced photodynamic therapy (CR-PDT) can tackle the tissue penetration limitation of traditional PDT. However, co-delivery of radionuclides and photosensitizer may cause continuous phototoxicity in normal tissues during the circulation. 5-aminolevulinic acid (ALA) which can intracellularly transform into photosensitive protoporphyrin IX (PpIX) is a cancer-selective photosensitizer with negligible side effect. However, the hydrophilic nature of ALA and the further conversion of PpIX to photoinactive Heme severely hinder the therapeutic benefits of ALA-based PDT. Herein, we developed an 89Zr-labeled, pH responsive ALA and artemisinin (ART) co-loaded liposome (89Zr-ALA-Liposome-ART) for highly selective cancer therapy. 89Zr can serve as the internal excitation source to self-activate PpIX for CR-PDT, and the photoinactive Heme can activate the chemotherapeutic effect of ART. The 89Zr-ALA-Liposome-ART exhibited excellent tumor inhibition capability in subcutaneous 4T1-tumor-bearing Balb/c mice via CR-PDT and chemotherapy. Combined with anti-PD-L1, the 89Zr-ALA-Liposome-ART elicited strong antitumor immunity to against tumor recurrence. A radiolabeled dual drug-loaded responsive liposome was designed to achieve tumor-selective Cerenkov radiation induced photodynamic therapy and combined chemotherapy. [Display omitted] • 89Zr labeled self-illuminated liposome facilitates PDT for deep tumors. • pH responsive release of prodrug ALA reduces the phototoxicity to normal tissue. • Heme generated from exogenous ALA activates the ART for combined chemotherapy. [ABSTRACT FROM AUTHOR]

The effectiveness of thermal ablation for the treatment of liver tumours is limited by the risk of incomplete ablation, which can result in residual tumours. Herein, an enhancement strategy is proposed based on the controlled release of Ganoderma applanatum polysaccharide (GAP) liposome–microbubble complexes (GLMCs) via ultrasound (US)-targeted microbubble destruction (UTMD) and sublethal hyperthermic (SH) field. GLMCs were prepared by conjugating GAP liposomes onto the surface of microbubbles via biotin–avidin linkage. In vitro , UTMD promotes the cellular uptake of liposomes and leads to apoptosis of M2-like macrophages. Secretion of arginase-1 (Arg-1) and transforming growth factor-beta (TGF-β) by M2-like macrophages decreased. In vivo , restriction of tumour volume was observed in rabbit VX2 liver tumours after treatment with GLMCs via UTMD in GLMCs + SH + US group. The expression levels of CD68 and CD163, as markers of tumour-associated macrophages (TAMs) in the GLMCs + SH + US group were reduced in liver tumour tissue. Decreased Arg-1, TGF-β, Ki67, and CD31 factors related to tumour cell proliferation and angiogenesis was evident on histological analysis. In conclusion, thermal/US-triggered drug release from GLMCs suppressed rabbit VX2 liver tumour growth in the SH field by inhibiting TAMs, which represents a potential approach to improve the effectiveness of thermal ablation. [Display omitted] • A novel-designed drug carrier (GAP loaded liposome microbubble complex, GLMC) could be dual thermal/ultrasound-triggered. • Activity and population of TAMs were inhibited via delivery of GLMCs. • GLMCs could suppress rabbit VX2 liver tumour growth with no obvious toxicity. • GLMCs could be imaged on contrast-enhanced ultrasonography. • Potential for enhancing effects of thermal ablation on liver tumours. [ABSTRACT FROM AUTHOR]

Checkpoint blockade immunotherapy (CBI) have exhibited remarkable benefits for cancer therapy. However, the low responsivity of CBI hinders its application in treatment of bladder cancer. Ferroptosis shows potential for increasing the responsivity of CBI by inducing immunogenic cell death (ICD) process. Herein, we developed a mitochondrial-targeted liposome loaded with brequinar (BQR) (BQR@MLipo) for enhancing the mitochondrial-related ferroptosis in bladder cancer in situ. It could be found that BQR@MLipo could selectively accumulate into mitochondria and inactivate dihydroorotate dehydrogenase (DHODH), which induced extensive mitochondrial lipid peroxidation and ROS, finally triggering ferroptosis of bladder cancer cells to boost the release of intracellular damage-associated molecular patterns (DAMPs) such as calreticulin (CRT), adenosine triphosphate (ATP), high mobility group box 1 (HMGB1). In addition, BQR@MLipo further promoted the release of mtDNA into the cytoplasm to activate the cGAS-STING pathway for the secretion of IFN-β, which would increase the cross-presentation of antigens by dendritic cells and macrophage phagocytosis. Furthermore, the in vivo studies revealed that BQR@MLipo could remarkably accumulate into the bladder tumor and successfully initiate the infiltration of CD8+ T cells into tumor microenvironment for enabling efficient CBI to inhibit bladder tumor growth. Therefore, BQR@MLipo may represent a clinically promising modality for enhancing CBI in bladder tumor. The mechanism of BQR@MLipo for enhancing mitochondria-related ferroptosis to potentiate checkpoint blockade immunotherapies. [Display omitted] [ABSTRACT FROM AUTHOR]

Antigen carriers that can selectively deliver antigens to antigen presenting cells and which can simultaneously activate these cells (adjuvant property) are necessary for efficient cancer immunotherapy or vaccination. Delivery of a model antigen into dendritic cell cytosol has been achieved by pH-responsive polymer-modified liposomes via destabilization of endosomal membranes responding to acidic pH, which impelled antigen-specific cellular immunity. Furthermore, β-glucan-based pH-responsive polysaccharides have shown not only cytosolic antigen delivery performance but also adjuvant property, which further heightened cellular immune responses. Because pH-responsive polysaccharides have anionic carboxy groups, cationic lipid was introduced to liposomes in this study to improve the modification efficiency of pH-responsive polysaccharides and to improve their adjuvanticity and immunity-inducing functions. Introduction of cationic lipids increased the amounts of polysaccharide derivatives on the liposome and increased the cellular association of the liposomes to dendritic cells. Liposomes containing β-glucan-based pH-responsive polysaccharides and cationic lipids increased cytokine production from dendritic cells much more than other polysaccharide derivatives did. Furthermore, through improvement of intra-tumoral immunosuppression and induction of antigen-specific cellular immunity, administering these liposomes impelled tumor suppression even with a small antigen dose. These results suggest that introducing cationic lipids and using pH-responsive polysaccharides having intrinsically adjuvant function are effective for producing liposomal nanovaccines showing strong immunity-inducing function. [Display omitted] • Cationic lipid inclusion promoted the polymer modification on the liposomes. • Cytoplasmic delivery of antigenic protein was achieved by the liposomes. • Cationic lipid inclusion significantly improved the adjuvanticity of the liposomes. • Intratumoral injection of the liposomes induced tumor growth suppression. • Liposome intratumoral injection improved immunosuppressive tumor microenvironments. [ABSTRACT FROM AUTHOR]

Radionuclide imaging and therapy are promising methods for controlling systemic cancers; however, their clinical application has been limited by excessive radionuclide accumulation in healthy tissues. To minimize radionuclide accumulation in non-cancerous tissues while ensuring sufficient build up in tumors, we aimed to develop a method that controlled the in vivo dynamics of radionuclides post-administration. To this end, we describe a novel strategy that combines liposomes, a potent carrier system for drug delivery, with unique radionuclide-ligand complexes based on 111In-ethylenedicysteine. Conventional 111In-ligand-complexes-carrying liposomes delivered substantial amounts of radionuclides to tumors; however, they also accumulated in the liver and spleen. In contrast, 111In-ethylenedicysteine-carrying liposomes greatly reduced non-specific accumulation, while being retained selectively at high doses within tumors. Liposomes were rapidly broken down in the liver, releasing encapsulated 111In-ligand complexes. Among the chelates used, only 111In-ethylenedicysteine could escape from the liver and be excreted in the urine. Instead, most liposomes remained intact in tumors, retaining the radionuclide-ligand complexes within them. Therefore, high tumor accumulation was obtained regardless of the type of 111In-ligand complexes in the liposomes. In vivo single photon emission computed tomography/computed tomography imaging with 111In-ethylenedicysteine-carrying liposomes accurately revealed tumor-selective radionuclide retention with little background. Hence, our new strategy could greatly enhance tumor-to-healthy tissue ratios, improve diagnostic imaging, boost therapeutic efficacy, reduce toxicity to healthy tissues, and facilitate radionuclide imaging and therapy. [Display omitted] • Novel strategy: liposomes+111In-ethylenedicysteine for precise radionuclide control. • Significantly reduced healthy tissue accumulation while preserving tumor targeting. • High tumor-to-healthy tissue ratio, precise imaging, and lower toxicity are achieved. • In vivo SPECT/CT imaging demonstrates tumor-selective radionuclide retention. • Potential for improved radionuclide imaging and radionuclide therapy for cancers. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are the major immune cells infiltrating the tumor microenvironment (TME) and typically exhibit an immunosuppressive M2-like phenotype, which facilitates tumor growth and promotes resistance to immunotherapy. Additionally, tumor cells tend to express high levels of CD47, a "don't eat me" signal, that obstructs macrophage phagocytosis. Consequently, re-educating TAMs in combination with CD47 blockage is promising to trigger intense macrophage immune responses against tumors. As a toll-like receptor 7/8 agonist, resiquimod (R848) possesses the capacity to re-educate TAMs from M2 type to M1 type. We found that intratumoral administration of R848 synergistically improved the antitumor immunotherapeutic effect of CV1 protein (a SIRPα variant with high antagonism to CD47). However, the poor bioavailability and potential toxicity of this combo strategy remain a challenge. Here, a TAMs-targeted liposome (named: R-LS/M/CV1) co-delivering R848 and CV1 protein was constructed via decorating mannose on the liposomal surface. R-LS/M/CV1 exhibited high abilities of targeting, re-education and pro-phagocytosis of tumor cells to M2 macrophages in vitro. Intratumoral administration of R-LS/M/CV1 remarkedly eliminated tumor burden in the MC38 tumor model via repolarization of TAMs to M1 type, pro-phagocytosis of TAMs against tumors, and recruitment of tumor-infiltrating T cells. More encouragingly, due to the double targeting to TAMs and tumor cells of mannose and CV1 protein, R-LS/M/CV1 effectively accumulated at the tumor site, thereby not only remarkedly inhibiting tumors, but also exerting no hematological and histopathological toxicity when administered systemically. Our integrated strategy based on re-educating TAMs and CD47 blockade provides a promising approach to trigger macrophage immune responses against tumors for immunotherapy. [Display omitted] • Mannose-modified R848 and CV1 co-delivered liposomes achieved targeting, repolarization, and pro-phagocytosis of TAMs. • Achieved binding of CV1 to the liposomal surface in a simple and site-specific manner, using DOGS-NTA-Ni. • Systemic administration of the co-delivery liposome remarkably suppressed tumor growth with no obvious toxicity. [ABSTRACT FROM AUTHOR]

Although nanocarriers have been widely applied in the delivery of anticancer drugs, many commercialized anticancer nanodrug systems still suffer from the problem of being easily trapped by lysosomes, which severely limits the drug delivery efficiency of a nanodrug system. Meanwhile, in drug-resistant tumors, the efflux of anticancer therapeutic drugs via the drug efflux transporters on the plasma membrane of cancer cells can significantly decrease the intracellular drug concentration and lead to the failure of the drug treatment. Here, we developed a small-molecule tyrosine kinase inhibitor (TKI)- and doxorubicin (Dox, a common anticancer drug)-loaded membrane fusion liposome (MFL) (termed Dox@Lapa-MFL) to achieve tumor cell membrane fusion-mediated drug delivery and enhanced chemotherapy of drug-resistant tumor. MFL could deliver drugs in a membrane fusion manner, circumventing the capture by lysosomes. Lapatinib, as the TKI doped in the MFL, could inhibit the efflux of Dox by ATP-binding cassette transporters (ABC transporters), further promoting the intracellular Dox accumulation. As a result, Dox achieved effective killing of drug-resistant tumors under the dual effect of MFL and lapatinib. To the best of our knowledge, it is the first example that employs membrane fusion-mediated TKI delivery for achieving tumor chemosensitization with good biosafety. This work presents an efficient and easily achievable strategy for treating drug-resistant tumors, which may hold promise for clinical applications. [Display omitted] • A membrane fusion liposome loaded with lapatinib and doxorubicin (Dox) is prepared. • It can realize membrane fusion-mediated drug delivery and avoid lysosomal trapping. • Lapatinib promotes the cellular accumulation of Dox by modulating ABC transporter. • Dox kills drug-resistant tumor cells due to lapatinib's chemosensitization effect. [ABSTRACT FROM AUTHOR]

Based on its ability to induce strong immunogenic cell death (ICD), chemodynamic therapy (CDT) was elaborately designed to combine with immunotherapy for a synergistic anticancer effect. However, hypoxic cancer cells can adaptively regulate hypoxia-inducible factor-1 (HIF-1) pathways, leading to a reactive oxygen species (ROS)-homeostatic and immunosuppressive tumor microenvironment. Consequently, both ROS-dependent CDT efficacy and immunotherapy are largely diminished, further lowering their synergy. Here, a liposomal nanoformulation co-delivering a Fenton catalyst copper oleate and a HIF-1 inhibitor acriflavine (ACF) was reported for breast cancer treatment. Through in vitro and in vivo experiments, copper oleate-initiated CDT was proven to be reinforced by ACF through HIF-1-glutathione pathway inhibition, thus amplifying ICD for better immunotherapeutic outcomes. Meanwhile, ACF as an immunoadjuvant significantly reduced the levels of lactate and adenosine, and downregulated the expression of programmed death ligand-1 (PD-L1), thereby promoting the antitumor immune response in a CDT-independent manner. Hence, the " one stone " ACF was fully taken advantage of to enhance CDT and immunotherapy (two birds), both of which contributed to a better therapeutic outcome. Scheme 1. Schematic diagram of LipoCu-OA/ACF to enhance chemodynamic-immunotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Ziconotide (ZIC) is an N-type calcium channel antagonist for treating severe chronic pain that is intolerable, or responds poorly to the administration of other drugs, such as intrathecal morphine and systemic analgesics. As it can only work in the brain and cerebrospinal fluid, intrathecal injection is the only administration route for ZIC. In this study, borneol (BOR)-modified liposomes (LIPs) were fused with exosomes from mesenchymal stem cells (MSCs) and loaded with ZIC to prepare microneedles (MNs) to improve the efficiency of ZIC across the blood-brain barrier. To evaluate local analgesic effects of MNs, the sensitivity of behavioral pain to thermal and mechanical stimuli was tested in animal models of peripheral nerve injury, diabetes-induced neuropathy pain, chemotherapy-induced pain, and ultraviolet-B (UV-B) radiation-induced neurogenic inflammatory pain. BOR-modified LIPs loaded with ZIC were spherical or nearly spherical, with a particle size of about 95 nm and a Zeta potential of −7.8 mV. After fusion with MSC exosomes, the particle sizes of LIPs increased to 175 nm, and their Zeta potential increased to −3.8 mV. The nano-MNs constructed based on BOR-modified LIPs had good mechanical properties and could effectively penetrate the skin to release drugs. The results of analgesic experiments showed that ZIC had a significant analgesic effect in different pain models. In conclusion, the BOR-modified LIP membrane-fused exosome MNs constructed in this study for delivering ZIC provide a safe and effective administration for chronic pain treatment, as well as great potential for clinical application of ZIC. [Display omitted] • To provide a transdermal delivery system for the delivery of ziconotide. • ZIC@MSCEXO/LIP-BOR can improve the ability of crossing the BBB effectively. • ZIC@MSCEXO/LIP-BOR have the characteristics of liposomes and exosomes. • Various pain models were established to evaluate the analgesic effect. • MN#ZIC@MSCEXO/LIP-BOR has high biocompatibility and analgesic effect. [ABSTRACT FROM AUTHOR]

Subunit proteins provide a safe source of antigens for vaccine development especially for intracellular infections which require the induction of strong cellular immune responses. However, those antigens are often limited by their low immunogenicity. In order to achieve effective immune responses, they should be encapsulated into a stable antigen delivery system combined with an appropriate adjuvant. As such cationic liposomes provide an efficient platform for antigen delivery. In the present study, we describe a liposomal vaccine platform for co-delivery of antigens and adjuvants able to elicit strong antigen-specific adaptive immune responses. Liposomes are composed of the cationic lipid dimethyl dioctadecylammonium bromide (DDAB), cholesterol (CHOL) and oleic acid (OA). Physicochemical characterization of the formulations showed that their size was in the range of ∼250 nm with a positive zeta potential which was affected in some cases by the enviromental pH facilitating endosomal escape of potential vaccine cargo. In vitro, liposomes were effectively taken up by bone marrow dendritic cells (BMDCs) and when encapsulated IMQ they promoted BMDCs maturation and activation. Upon in vivo intramuscular administration, liposomes' active drainage to lymph nodes was mediated by DCs, B cells and macrophages. Thus, mice immunization with liposomes having encapsulated LiChimera, a previously characterized anti-leishmanial antigen, and IMQ elicited infiltration of CD11blow DCs populations in draining LNs followed by increased antigen-specific IgG, IgG2a and IgG1 levels production as well as indcution of antigen-specific CD4+ and CD8+ T cells. Collectively, the present work provides a proof-of-concept that cationic liposomes composed of DDAB, CHOL and OA adjuvanted with IMQ provide an efficient delivery platform for protein antigens able to induce strong adaptive immune responses via DCs targeting and induction of maturation. [Display omitted] • Cationic liposomes were prepared for efficient subunit vaccine delivery. • Liposomes promoted antigen delivery to draining lymph nodes via APCs trafficking. • IMQ-loaded liposomes triggered DCs maturation. • Mice immunization induced antigen-specific humoral and cellular immune responses. [ABSTRACT FROM AUTHOR]

Nanocarriers entering the body are usually coated by plasma protein, leading to a protein "corona" easily recognized by tissues and cells. Adjusting the composition of protein coronas may be an efficient way to change the properties and behavior of nanoparticles in vivo. In this study, we modified doxorubicin-loaded liposomes (Lip/DOX) with an albumin-binding domain (ABD) to prepare nanoparticles (ABD-Lip/DOX) that can specifically bind to albumin and form albumin-based protein coronas in vivo for targeted tumor therapy. The prepared liposomes were spherical with a particle size of about 100 nm. After incubating the liposomes with rat serum, the albumin content was eight times higher on ABD-Lip than on control liposomes. ABD-Lip significantly inhibited adsorption of IgG and complement activation in rat serum in vitro , while corona-coated ABD-Lip was internalized to a significantly greater extent than corona-coated control liposomes. In addition, ABD-Lip showed longer blood circulation time, higher tumor accumulation and greater antitumor efficacy than control liposomes in mice bearing 4 T1 tumors, while both liposome formulations showed similar biocompatibility. These results confirm that adjusting the component of protein coronas around nanoparticles can improve their therapeutic efficacy. [Display omitted] [ABSTRACT FROM AUTHOR]

Cancer vaccine efficacy is limited by the immunosuppressive nature of the tumor microenvironment created by inflammation, immune inhibitory factors, and regulatory T cells (Tregs). Inspired by the role of cyclooxygenase-2 (COX-2) in inflammation in the tumor site, we proposed that normalization of the tumor microenvironment by celecoxib as a COX-2 inhibitor might improve the efficacy of Dendritic Cell (DC) therapy in a melanoma model. In the present study, liposomal celecoxib (Lip-CLX) was combined with ex vivo generated DC vaccines pulsed with gp100 peptide (in liposomal and non-liposomal forms) for prophylactic and therapeutic evaluation in the B16F10 melanoma model. Tumor site analysis by flow cytometry demonstrated that intravenous administration of Lip-CLX at a dose of 1 mg/kg in four doses effectively normalized the tumor microenvironment by reducing Tregs and IL-10 production. Furthermore, in combination with DC vaccination (DC + Lip-peptide+Lip-CLX), it significantly increased tumor-infiltrating CD4+ and CD8+ T cells and secretion of IFN-γ. This combinatorial strategy produced an effective prophylactic and therapeutic antitumor response, which reduced tumor growth and prolonged the overall survival. In conclusion, our findings suggest that the liposomal celecoxib targets the inhibitory mechanisms of the tumor microenvironment and broadens the impact of DC therapy to improve the outcome of immunotherapy in solid tumors. [Display omitted] • Liposomal celecoxib inhibits the regulatory T cells and immunosuppression in the tumor microenvironment • COX-2 inhibition combined with dendritic cell therapy induces robust CD8+ T cell responses in mice • Combination therapy exerts strong anti-tumor efficacy in the prophylactic and therapeutic melanoma model • Celecoxib, an anti-inflammatory drug, has promising potential for the advancement of immunotherapy efficacy in solid tumors [ABSTRACT FROM AUTHOR]

Image guided nose-to-brain drug delivery provides a non-invasive way to monitor drug delivered to the brain, and the intranasal administration could increase effective dose via bypassing Blood Brain Barrier (BBB). Here, we investigated the imaging of liposome-based drug delivery to the brain via intranasal administration, in which the liposome could penetrate mucus and could be detected by chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) at 3T field strength. Liposomes were loaded with a computed tomography (CT) contrast agent, iohexol (Ioh-Lipo), which has specific amide protons exchanging at 4.3 ppm of Z -spectrum (or CEST spectrum). Ioh-Lipo generated CEST contrasts of 35.4% at 4.3 ppm, 1.8% at −3.4 ppm and 20.6% at 1.2 ppm in vitro. After intranasal administration, these specific CEST contrasts were observed in both olfactory bulb (OB) and frontal lobe (FL) in the case of 10% polyethylene glycol (PEG) Ioh-Lipo. We observed obvious increases in CEST contrast in OB half an hour after the injection of 10% PEG Ioh-Lipo, with a percentage increase of 62.0% at 4.3 ppm, 10.9% at −3.4 ppm and 25.7% at 1.2 ppm. Interestingly, the CEST map at 4.3 ppm was distinctive from that at −3.4 pm and 1.2 ppm. The highest contrast of 4.3 ppm was at the external plexiform layer (EPL) and the region between left and right OB (LROB), while the CEST contrast at −3.4 ppm had no significant difference among all investigated regions with slightly higher signal in olfactory limbus (OL, between OB and FL) and FL, as validated with histology. While no substantial increase of CEST contrast at 4.3 ppm, −3.4 ppm or 1.2 ppm was observed in OB and FL when 1% PEG Ioh-Lipo was administered. We demonstrated for the first time the feasibility of non-invasively detecting the nose-to-brain delivery of liposomes using CEST MRI. This multiple-contrast approach is necessary to image the specific distribution of iohexol and liposome simultaneously and independently, especially when designing drug carriers for nose-to-brain drug delivery. [Display omitted] [ABSTRACT FROM AUTHOR]

Alveolar macrophages play a crucial role in the initiation and resolution of the immune response in the lungs. Pro-inflammatory M1 alveolar macrophages are an interesting target for treating inflammatory and infectious pulmonary diseases. One commune targeting strategy is to use nanoparticles conjugated with hyaluronic acid, which interact with CD44 overexpressed on the membrane of those cells. Unfortunately, this coating strategy may be countered by the presence on the surface of the nanoparticles of a poly(ethylene glycol) corona employed to improve nanoparticles' diffusion in the lung mucus. This study aims to measure this phenomenon by comparing the behavior in a murine lung inflammation model of three liposomal platforms designed to represent different poly(ethylene glycol) and hyaluronic acid densities (Liposome-PEG, Liposome-PEG-HA and Liposome-HA). In this work, the liposomes were obtained by a one-step ethanol injection method. Their interaction with mucin and targeting ability toward pro-inflammatory macrophages were then investigated in vitro and in vivo in a LPS model of lung inflammation. In vitro , poly(ethylene glycol) free HA-liposomes display a superior targeting efficiency toward M1 macrophages, while the addition of poly(ethylene glycol) induces better mucus mobility. Interestingly in vivo studies revealed that the three liposomes showed distinct cell specificity with alveolar macrophages demonstrating an avidity for poly(ethylene glycol) free HA-liposomes, while neutrophils favored PEGylated liposomes exempt of HA. Those results could be explained by the presence of two forces exercising a balance between mucus penetration and receptor targeting. This study corroborates the importance of considering the site of action and the targeted cells when designing nanoparticles to treat lung diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Liposomes are promising targeted drug delivery systems with the potential to improve the efficacy and safety profile of certain classes of drugs. Though attractive, there are unique analytical challenges associated with the development of liposomal drugs including human dose prediction given these are multi-component drug delivery systems. In this study, we developed a multimodal imaging approach to provide a comprehensive distribution assessment for an antibacterial drug, GSK2485680, delivered as a liposomal formulation (Lipo680) in a mouse thigh model of bacterial infection to support human dose prediction. Positron emission tomography (PET) imaging was used to track the in vivo biodistribution of Lipo680 over 48 h post-injection providing a clear assessment of the uptake in various tissues and, importantly, the selective accumulation at the site of infection. In addition, a pharmacokinetic model was created to evaluate the kinetics of Lipo680 in different tissues. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was then used to quantify the distribution of GSK2485680 and to qualitatively assess the distribution of a liposomal lipid throughout sections of infected and non-infected hindlimb tissues at high spatial resolution. Through the combination of both PET and MALDI IMS, we observed excellent correlation between the Lipo680-radionuclide signal detected by PET with the GSK2485680 and lipid component signals detected by MALDI IMS. This multimodal translational method can reduce drug attrition by generating comprehensive biodistribution profiles of drug delivery systems to provide mechanistic insight and elucidate safety concerns. Liposomal formulations have potential to deliver therapeutics across a broad array of different indications, and this work serves as a template to aid in delivering future liposomal drugs to the clinic. [Display omitted] [ABSTRACT FROM AUTHOR]

Adrenergic nerves, which are innervated in the tumor, regulate tumor initiation, angiogenesis, and the establishment of the tumor immunosuppressive microenvironment. The study aimed to evaluate the effectiveness of propranolol liposomes (Lipo pro) in inhibiting adrenergic nerve signaling in cancer therapy. Lipo pro significantly regulated the distribution of tumor microenvironment adrenergic nerves, tumor blood vessels, and immunosuppressive microenvironment. Furthermore, it displayed considerable therapeutic effects on prostatic cancer, pancreatic ductal adenocarcinoma, and melanoma. The combination therapeutic regimen, in which Lipo pro was the primary treatment and was supplemented by chemotherapy, showed significant advantages over any single treatment, effectively restraining tumor growth in situ and metastasis, thereby prolonging the survival of mice. This study established a proof-of-concept by targeting tumor adrenergic nerve signaling for cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Upon exhaustive research, the transdermal drug delivery system (TDDS) has appeared as a potential, well-accepted, and popular approach to a novel drug delivery system. Ease of administration, easy handling, minimum systemic exposure, least discomfort, broad flexibility and tunability, controlled release, prolonged therapeutic effect, and many more perks make it a promising approach for effective drug delivery. Although, the primary challenge associated is poor skin permeability. Skin is an intact barrier that serves as a primary defense mechanism to preclude any foreign particle's entry into the body. Owing to the unique anatomical framework, i.e. , compact packing of stratum corneum with tight junction and fast anti-inflammatory responses, etc. , emerged as a critical physiological barrier for TDDS. Fusion with other novel approaches like nanocarriers, specially designed transdermal delivery devices, permeation enhancers, etc. , can overcome the limitations. Utilizing such strategies, some of the products are under clinical trials, and many are under investigation. This review explores all dimensions that overcome poor permeability and allows the drug to attain maximum potential. The article initially compiles fundamental features, components, and design of TDDS, followed by critical aspects and various methods, including in vitro , ex vivo , and in vivo methods of assessing skin permeability. The work primarily aimed to highlight the recent advancement in novel strategies for effective transdermal drug delivery utilizing active methods like iontophoresis, electroporation, sonophoresis, microneedle, needleless jet injection, etc. , and passive methods such as the use of liposomes, SLN, NLC, micro/nanoemulsions, dendrimers, transferosomes, and many more nanocarriers. In all, this compilation will provide a recent insight on the novel updates along with basic concepts, the current status of clinical development, and challenges for the clinical translation of TDDS. [Display omitted] [ABSTRACT FROM AUTHOR]

Metal complexes are of increasing interest as pharmaceutical agents in cancer diagnostics and therapeutics, while some of them suffer from issues such as limited water solubility and severe systemic toxicity. These drawbacks severely hampered their efficacy and clinical applications. Liposomes hold promise as delivery vehicles for constructing metal complex-based liposomes to maximize the therapeutic efficacy and minimize the side effects of metal complexes. This review provides an overview on the latest advances of metal complex-based liposomal delivery systems. First, the development of metal complex-mediated liposomal encapsulation is briefly introduced. Next, applications of metal complex-based liposomes in a variety of fields are overviewed, where drug delivery, cancer imaging (single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI)), and cancer therapy (chemotherapy, phototherapy, and radiotherapy) were involved. Moreover, the potential toxicity, action of toxic mechanisms, immunological effects of metal complexes as well as the advantages of metal complex-liposomes in this content are also discussed. In the end, the future expectations and challenges of metal complex-based liposomes in clinical cancer therapy are tentatively proposed. [Display omitted] [ABSTRACT FROM AUTHOR]

Some chemotherapy can damage tumor cells, releasing damage-related molecular patterns including ATP to improve immunological recognition against the tumor by immunogenic cell death (ICD). However, the immune-stimulating ATP may be rapidly degraded into immunosuppressive adenosine by highly expressed CD39 and CD73 in the tumor microenvironment, which leads to immune escape. Based on the above paradox, a liposome nanoplatform combined with ICD inducer (oxaliplatin) and CD39 inhibitor (POM-1) is designed for immunochemotherapy. The liposomes efficiently load the phospholipid-like oxaliplatin prodrug, and the cationic charged surface could adsorb POM-1. Rationally designed DSPE-PEG n -pep, on the one hand, could cover and hide POM-1 to avoid systematic toxicity and, on the other, achieve a response and charge reversal to favor POM-1 shedding and tumor deep penetration. This combination maximizes the ICD effect, and takes two-pronged advantage of stimulating the immune response and relieving immune suppression. The designed POL can effectively inhibit the growth of in situ, lung metastasis and postoperative recurrence melanoma model and form long-term immune memory. With the powerful clinical transformation potential of nanoliposome platforms, this new synergistic strategy is expected to enhance anticancer effects safely and effectively. [Display omitted] [ABSTRACT FROM AUTHOR]

Acute Respiratory Distress Syndrome (ARDS), associated with Covid-19 infections, is characterized by diffuse lung damage, inflammation and alveolar collapse that impairs gas exchange, leading to hypoxemia and patient' mortality rates above 40%. Here, we describe the development and assessment of 100-nm liposomes that are tailored for pulmonary delivery for treating ARDS, as a model for lung diseases. The liposomal lipid composition (primarily DPPC) was optimized to mimic the lung surfactant composition, and the drug loading process of both methylprednisolone (MPS), a steroid, and N -acetyl cysteine (NAC), a mucolytic agent, reached an encapsulation efficiency of 98% and 92%, respectively. In vitro, treating lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages with the liposomes decreased TNFα and nitric oxide (NO) secretion, while NAC increased the penetration of nanoparticles through the mucus. In vivo, we used LPS-induced lung inflammation model to assess the accumulation and therapeutic efficacy of the liposomes in C57BL/6 mice, either by intravenous (IV), endotracheal (ET) or IV plus ET nanoparticles administrations. Using both administration methods, liposomes exhibited an increased accumulation profile in the inflamed lungs over 48 h. Interestingly, while IV-administrated liposomes distributed widely throughout the lung, ET liposomes were present in lungs parenchyma but were not detected at some distal regions of the lungs, possibly due to imperfect airflow regimes. Twenty hours after the different treatments, lungs were assessed for markers of inflammation. We found that the nanoparticle treatment had a superior therapeutic effect compared to free drugs in treating ARDS, reducing inflammation and TNFα, IL-6 and IL-1β cytokine secretion in bronchoalveolar lavage (BAL), and that the combined treatment, delivering nanoparticles IV and ET simultaneously, had the best outcome of all treatments. Interestingly, also the DPPC lipid component alone played a therapeutic role in reducing inflammatory markers in the lungs. Collectively, we show that therapeutic nanoparticles accumulate in inflamed lungs holding potential for treating lung disorders. In this study we compare intravenous versus intratracheal delivery of nanoparticles for treating lung disorders, specifically, acute respiratory distress syndrome (ARDS). By co-loading two medications into lipid nanoparticles, we were able to reduce both inflammation and mucus secretion in the inflamed lungs. Both modes of delivery resulted in high nanoparticle accumulation in the lungs, intravenously administered nanoparticles reached lung endothelial while endotracheal delivery reached lung epithelial. Combining both delivery approaches simultaneously provided the best ARDS treatment outcome. [Display omitted] [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive brain tumor with poor prognosis and frequent recurrence. The blood-brain barrier (BBB), blood-brain tumor barrier (BBTB) hinder the entry of therapeutics into the glioma region. Vasculogenic mimicry (VM) formed by invasive glioma cells is also related to recurrence of GBM. VAP is a D-peptide ligand of GRP78 protein overexpressed on BBTB, VM, and glioma cells but not on normal tissues. Besides, p-hydroxybenzoic acid (pHA) can effectively traverse the BBB. Herein we developed an all-stage glioma-targeted cabazitaxel (CBZ) nanocrystal loaded liposome modified with a "Y" shaped targeting ligand composed of pHA and VAP (pV-Lip/cNC). The pure drug nanocrystal core provided high drug loading, while lipid membrane promoted the stability and circulation time. pV-Lip/cNC exhibited excellent glioma homing, barriers crossing, and tumor spheroid penetrating capability in vitro. Treatment of pV-Lip/cNC displayed enhanced CBZ accumulation in glioma and anti-glioma effect with a median survival time (53 days) significantly longer than that of cNC loaded liposomes modified with either single ligand (42 days for VAP and 45 days for pHA) in the murine orthotopic GBM model. These results indicated pV-Lip/cNC could traverse the BBB and BBTB, destruct VM, and finally kill glioma cells to realize all-stage glioma therapy. [Display omitted] • Lipid membrane coating endowed cabazitaxel nanocrystals with enhanced stability, longer retention time, and a surface modified platform. • The "Y" shaped all target ligand preserved the functions of both moieties at less PEG-DSPE modification density. • All-stage targeted delivery based on cabazitaxel nanocrystal loaded liposome efficiently prolonged the survival time of mice bearing orthotopic glioblastoma. [ABSTRACT FROM AUTHOR]

The administration of liposomes via nose-to-brain delivery is expected to become a strategy for efficient drug delivery to the central nervous system. Efficient nose-to-brain delivery and the kinetics of drugs administered in this manner depend on the properties of liposomes. However, there is a lack of basic knowledge of which liposomes are suitable for this purpose. Here, a qualitative study of intranasally administered liposomes (positively charged, neutral, and negatively charged, with or without polyethylene glycol [PEG] modification; particle size <100 nm) was performed to elucidate their dynamics in the brain and spinal cord. Additionally, a quantitative investigation was performed to ascertain their distribution in each part of the brain and spinal cord. The effects of liposome surface charge and PEG modification on the kinetics and distribution post intranasal administration were investigated via two experiments. Qualitative evaluation was performed via ex vivo observation after intranasal administration of fluorescently labeled liposomes. Neutral PEG-modified liposomes were distributed throughout the brain and spinal cord 60 min after administration, and the fluorescence intensity increased with time. By contrast, non-PEG-modified neutral liposomes showed particularly strong fluorescence in the olfactory bulb, and the fluorescence was localized in the anterior part of the brain. Positively charged liposomes showed low fluorescence around the lateral part of the brain and lumbar spinal cord 60 min after administration. Low fluorescence was observed in the whole brain and spinal cord, with strong fluorescence being observed in the olfactory bulb after 120 min of administration. Negatively charged liposomes showed no fluorescence at 60 min after administration, but low fluorescence was observed throughout the brain and spinal cord 120 min after administration. We quantified the radioactivity in the brain and spinal cord after intranasal administration of radioisotope-labeled liposomes. Neutral liposomes showed the highest distribution by area under the drug concentration-time curve (AUC 60–120) in the brain and spinal cord compared to other liposomes. Compared with negatively charged liposomes, positively charged liposomes had a higher distribution in the olfactory bulb and forebrain, while negatively charged liposomes had a higher distribution in the hindbrain and bulbospinal tract cord. In addition, the distribution of PEG-modified neutral liposomes in the brain and spinal cord was significantly enhanced compared to that of non-PEG-modified neutral liposomes after 90 min of intranasal administration. These results indicate that surface charge and PEG modification strongly affect the efficiency of nose-to-brain delivery kinetics, and that PEG-modified neutral liposomes are excellent carriers for drug delivery to a wide area of the brain and spinal cord. [Display omitted] • Neutral liposomes had higher distribution in the brain and spinal cord. • PEG modification improved liposome distribution in brain. • PEG modification improved liposome distribution in spinal cord. • PEG-modified neutral liposomes suitable as drug delivery carriers. [ABSTRACT FROM AUTHOR]

RGD motif has long been exploited as a versatile tool for targeted drug delivery. However, there are so far no successful clinical translations of RGD functionalized nanomedicines. The lack of comprehensive understanding of their in vivo delivery process poses one of the main obstacles. As a reflection on cRGD-enabled targeting delivery, herein the in vivo fate of cyclic RGD peptide functionalized liposome (cRGD-sLip) and its fundamental mechanism are investigated. cRGD-sLip demonstrates incredibly rapid blood clearance and massive mononuclear phagocytic system (MPS) accumulation after intravenous injection. Phagocytes actively capture cRGD-sLip by recognizing α v β 3 integrins and scavenger receptors, urging reinterrogation of RGD enabled targeting delivery. Intracellular infection with microbes invading and persisting in the phagocytic system poses serious threats to global public health. Most antimicrobial agents are unable to penetrate through host cell membrane and achieve optimal intracellular therapeutic concentration, resulting in ineffective bacterial killing. By leveraging the rapid phagocytic uptake, cRGD-sLip demonstrates the capability to facilitate effective targeted drug delivery to bacteria infected macrophages and successfully reduce the bacterial burden in a murine intracellular Methicillin-resistant Staphylococcus aureus (MRSA) infection model, verifying the potential value of cRGD-sLip in improving therapeutic efficacy of existing antibiotics in the treatment of intracellular bacterial infection. cRGD-sLip demonstrates rapid blood clearance and phagocyte capture by recognizing integrins and scavenger receptors and serves to improve therapeutic efficacy of existing antibiotics in the treatment of intracellular bacterial infection. [Display omitted] • cRGD modification leads to rapid blood clearance and MPS accumulation of liposomes. • Phagocytes capture cRGD-sLip by recognizing α v β 3 integrin and scavenger receptors. • Heavy phagocytosis urges re-interrogation of RGD enabled targeting delivery. • cRGD-sLip offer a promising antibiotic carrier for intracellular bacteria clearance. [ABSTRACT FROM AUTHOR]

Adjuvant loaded nanoparticles are a potent strategy for developing effective combined cancer immunotherapies. A polyinosinic-polycytidylic acid (poly I:C) is a ligand for toll-like receptor 3 and a promising cancer adjuvant. However, regarding intravenous administration, the potential for and the mechanism of poly I:C loaded nanoparticles as a cancer vaccine are largely unknown. We investigated the effects of using a combination of poly I:C and an antigen loaded liposome for cancer immunotherapy and a key process for achieving effective antitumor immunity of the liposome system under conditions of intravenous vaccination. A poly I:C and ovalbumin (OVA) loaded octaarginine (R8) modified liposome (PoIC/OVA-R8L) drastically inhibited the systemic cytokine production derived from the poly I:C intravenous injection. Treatment with PoIC/OVA-R8L improved the immune status in B16-OVA tumors to an inflamed immune status and induced a significant combined antitumor effect with the anti-programmed cell death 1 ligand (PD-L1). In a mechanistic analysis compared with a high dose of the free form of poly I:C, interestingly, local cytokine production, maturation of antigen presenting cells and antigen presentation were comparable. Conversely, significant differences were identified in the processes after OVA-specific CTL generation. Collectively, our findings have implications for the development of intravenous liposomal vaccines. [Display omitted] • Liposomal poly I:C inhibits the systemic production of inflammatory cytokines. • The intravenous injection of liposomal poly I:C cooperates with anti-PD-L1. • Innate cytokine responses occur in the liver, and not the spleen. • Key process of enhancement by liposomal poly I:C involves the generation of killer T cells. [ABSTRACT FROM AUTHOR]

There is an urgent need to develop nanocarriers for the treatment of glioblastoma multiforme (GBM). Using co-registered positron emission tomography (PET) and magnetic resonance (MR) images, here we performed systematic studies to investigate how a nanocarrier's size affects the pharmacokinetics and biodistribution in rodents with a GBM xenograft. In particular, highly stable, long-circulating three-helix micelles (3HM), based on a coiled-coil protein tertiary structure, were evaluated as an alternative to larger nanocarriers. While the circulation half-life of the 3HM was similar to 110-nm PEGylated liposomes (t1/2=15.5 and 16.5h, respectively), the 20-nm micelles greatly enhanced accumulation within a U87MG xenograft in nu/nu rats after intravenous injection. After accounting for tumor blood volume, the extravasated nanoparticles were quantified from the PET images, yielding ~0.77%ID/cm(3) for the micelles and 0.45%ID/cm(3) for the liposomes. For GBM lesions with a volume greater than 100mm(3), 3HM accumulation was enhanced both within the detectable tumor and in the surrounding brain parenchyma. Further, the nanoparticle accumulation was shown to extend to the margins of the GBM xenograft. In summary, 3HM provides an attractive nanovehicle for carrying treatment to GBM.

Breast cancer is the most common cancer among women and a leading cause of death worldwide. Triple negative breast cancer (TNBC) is a highly aggressive subtype which is the most challenging to treat. Due to heterogeneity and a lack of specific molecular targets, small molecule-based chemotherapy is the preferred course of treatment. However, these drugs have high toxicity due to off-target effects on healthy tissues, and tumors may develop resistance. Here, we present a polyethylene glycol-modified nanoscale liposomal formulation (LipoRV) of a new anthraquinone derivative which has potent effects on multiple TNBC cell lines. LipoRV readily inhibited the cell cycle, induced cell apoptosis, and reduced long-term proliferative potential of TNBC cells. In a xenograft animal model, LipoRV successfully cleared tumors and demonstrated a good safety profile, without detrimental effects on biochemical markers. Finally, RNA sequencing of LipoRV-treated TNBC cells was carried out, indicating that LipoRV may have immunomodulatory properties. These findings demonstrate that a liposomal anthraquinone-based molecule has excellent promise for TNBC therapy in the future. [Display omitted] [ABSTRACT FROM AUTHOR]

The multidisciplinary field of photodynamic therapy (PDT) is a combination of photochemistry and photophysics sciences, which has shown tremendous potential for cancer therapy application. PDT employs a photosensitizing agent (PS) and light to form cytotoxic reactive oxygen species and subsequently oxidize light-exposed tissue. Despite numerous advantages of PDT and enormous progress in this field, common PSs are still far from ideal treatment because of their poor permeability, non-specific phototoxicity, side effects, hydrophobicity, weak bioavailability, and tendency to self-aggregation. To circumvent these limitations, PS can be encapsulated in liposomes, an advanced drug delivery system that has demonstrated the ability to enhance drug permeability into biological membranes and loading both hydrophobic and lipophilic agents. Moreover, liposomes can also be coated by targeting agents to improve delivery efficiency. The present review aims to summarize the principles of PDT, various PS generations, PS-loaded nanoparticles, liposomes, and their impact on PDT, then discuss recent photodynamic cancer therapy strategies using liposomes as PS-loaded vectors, and highlight future possibilities and perspectives. [Display omitted] [ABSTRACT FROM AUTHOR]

Neutrophils, the most abundant leukocytes in human peripheral blood, are important effector cells that mediate the inflammatory response. During neutrophil dysfunction, excessive activation and uncontrolled infiltration are the core processes in the progression of inflammation-related diseases, including severe coronavirus disease-19 (COVID-19), sepsis, etc. Herein, we used sialic acid-modified liposomal doxorubicin (DOX-SAL) to selectively target inflammatory neutrophils in the peripheral blood and deliver DOX intracellularly, inducing neutrophil apoptosis, blocking neutrophil migration, and inhibiting the inflammatory response. Strong selectivity resulted from the specific affinity between SA and L-selectin, which is highly expressed on inflammatory neutrophil membranes. In inflammation models of acute lung inflammation/injury (ALI), sepsis, and rheumatoid arthritis (RA), DOX-SAL suppressed the inflammatory response, increased the survival of mice, and delayed disease progression, respectively. Moreover, DOX-SAL restored immune homeostasis in the body, without side effects. We have presented a targeted nanocarrier drug delivery system that can block the recruitment of inflammatory neutrophils, enabling specific inhibition of the core disease process and the potential to treat multiple diseases with a single drug. This represents a revolutionary treatment strategy for inflammatory diseases caused by inappropriate neutrophil activation. [Display omitted] • Neutrophils activation up-regulated L-selectin to mediate DOX-SALs uptake. • DOX-SALs promoted neutrophil apoptosis by releasing doxorubicin. • DOX-SALs blocked neutrophil recruitment to inhibited acute lung injury. • DOX-SALs improved sepsis survival and maintained neutrophil generation in marrow. • DOX-SALs delayed the progression of rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Cyanide induces acute lethal poisoning resulting from inhibition of cytochrome c oxidase located in the complex IV (Complex IV) of mitochondria. However, current therapies for cyanide poisoning using hydroxocobalamin and nitrous acid compounds remain a clinical issue. Here, we show that liposome-encapsulated methemoglobin (metHb@Lipo), nanosized biomimetic red blood cells, replicate the antidotal mechanism of nitrous acid compounds against cyanide poisoning, achieving superior efficacy and fast action with no adverse effects. The structure of metHb@Lipo, which consists of concentrated methemoglobin in its aqueous core and a lipid membrane resembling the red blood cell membrane, provides favorable characteristics as a cyanide antidote, such as binding properties and membrane permeability. Upon cyanide exposure, metHb@Lipo maintained the mitochondrial function in PC12 cells, resulting in a cell viability comparable to treatment with nitrous acid compounds. In a mouse model of cyanide poisoning, metHb@Lipo treatment dramatically improved mortality with a rapid recovery from the symptoms of cyanide poisoning compared to treatment with nitrous acid compounds. Furthermore, metHb@Lipo also possesses satisfactory pharmacokinetic properties without long-term bioaccumulation and toxicity. Our findings showed a novel concept to develop drugs for cyanide poisoning and provide a promising possibility for biomimetic red blood cell preparations for pharmaceutical applications. [Display omitted] • metHb@Lipo is encapsulated methemoglobin in liposome, which mimics red blood cell. • metHb@Lipo replicates the antidotal mechanism of nitrite against cyanide poisoning. • metHb@Lipo possesses superior antidotal effect than nitrite and hydroxocobalamin. • metHb@Lipo has favorable pharmacokinetic properties and biocompatibility. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade (ICB) treatment is promising for the clinical therapy of numerous malignancies. However, most cancer patients rarely benefit from such single-agent immunotherapies because of the complexity of both the tumor and tumor microenvironment. A tumor-specific liposomal vehicle (DOX-SAL) modified with a sialic acid-cholesterol conjugate (SA-CH) and remotely loaded with doxorubicin (DOX) is herein reported for improving chemoimmunotherapy. The intravenous administration of DOX-SAL dramatically downregulates tumor-associated macrophage (TAM)-mediated immunosuppression, inhibits immunoregulatory functions, and promotes intratumoral infiltration of CD8+ T cells. Compared to conventional liposomes, DOX-SAL-mediated combination therapy with a PD-1-blocking monoclonal antibody (aPD-1 mAb) almost completely eliminates B16F10 tumors and efficiently inhibits 4T1 tumors. Moreover, cancer stem cells exhibit efficient tumor-initiating, tumor-propagating, and immunosuppressive tumor microenvironment-shaping capabilities. To further improve the treatment efficacy of an immunologically "cold" tumor, metformin (MET), which selectively eradicates breast cancer tumor stem cells, is co-encapsulated with DOX into liposomes to develop DOX/MET-SAL. The combination therapy with DOX/MET-SAL and aPD-1 mAb in a 4T1 orthotopic mouse model indicates their synergetic benefit on primary tumor inhibition, metastasis suppression, and survival rate improvement. Thus, the multifunctional liposomal platform has potential value for ICB combination immunotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Chemo-immunotherapy based on immunogenic cell death (ICD) is a promising strategy for cancer therapy. However, the effective ICD requires a high dosage of ICD stimulus, which could be associated to a dose-dependent toxicity. Therefore, in this study, a liposome remote-loaded with shikonin (a potent ICD stimulus) was developed, with the ability to effectively induce ICD at high dosage in vivo. However, a hepatotoxic effect was observed. To circumvent this problem, shikonin was combined with the anthracycline mitoxantrone or doxorubicin to develop co-loaded liposomes inducing a synergistic ICD effect and cytotoxicity to tumor cells. Cytotoxicity and uptake experiment in vitro were performed to analyze the optimal synergistic ratio of shikonin and anthracyclines based on a "formulated strategy". Interestingly, copper mediated co-loaded liposomes resulted in a pH and GSH dual-responsive release property. More importantly, pharmacokinetics and tumor biodistribution studies revealed an outstanding capacity of ratiometric delivery of dual drugs. Thus, the dual-loaded liposome enhanced the antitumor effect by the stimulation of a robust immune response at lower doses of the drugs with a higher safety compared to single-loaded liposomes. Summarized, the current work provided a reference for a rational design and development of liposomal co-delivery system of drugs and ICD-induced chemo-immunotherapy, and established a potential clinical application of shikonin-based drug combinations as a new chemo-immunotherapeutic strategy for cancer treatment. [Display omitted] • Rational design of liposomes loaded drugs with different physicochemical properties were systematically studied. • Copper mediated co-loaded liposomes presented pH and GSH dual-responsive release properties. • Shikonin and anthracyclines dual-loaded liposomes provide a new chemo-immunotherapeutic strategy for cancer treatment. [ABSTRACT FROM AUTHOR]

Mice are arguably the most important tool in the preclinical evaluation of liposomes; however, the effects of inter-strain physiological variabilities on in vivo performance of liposomes have been seriously overlooked. The present study validated that plasma proteins (PPs) and the capability of mononuclear phagocyte system (MPS) (typically expressed by phagocytosis rate, K) were mice strain-dependent. Physiological variabilities in PPs and the phagocytosis rate jointly contributed to the inter-strain inconsistency of pharmacokinetic (PK) profiles of liposomes. For the PPs sensitive liposomes (such as plain PEGylated liposomes and folic acid functionalized PEGylated liposomes), inter-strain variabilities in PK profiles could be calibrated using the corrected phagocytic rate (K C = K×(c × Ig)/(alb×apo)), where c, Ig, alb and apo were respective the total content of complement proteins, immunoglobulins, albumin and apolipoproteins. While for the PPs insensitive liposomes (e.g., cRGD functionalized liposomes), phagocytic rate could be directly used to calibrate inter-strain difference of liposome PK profiles. Our data also warn that the reciprocal interaction between payloads and organisms would be much more complicated than that between liposomes and organisms, thus independent investigation should be conducted for each individual therapeutic agent. [Display omitted] [ABSTRACT FROM AUTHOR]

Advancements in liposomal drug delivery have produced long circulating and very stable drug formulations. These formulations minimize systemic exposure; however, unfortunately, therapeutic efficacy has remained limited due to the slow diffusion of liposomal particles within the tumor and limited release or uptake of the encapsulated drug. Here, the carboxyl-terminated CRPPR peptide, with affinity for the receptor neuropilin-1 (NRP), which is expressed on both endothelial and cancer cells, was conjugated to liposomes to enhance the tumor accumulation. Using a pH sensitive probe, liposomes were optimized for specific NRP binding and subsequent cellular internalization using in vitro cellular assays. Liposomes conjugated with the carboxyl-terminated CRPPR peptide (termed C-LPP liposomes) bound to the NRP-positive primary prostatic carcinoma cell line (PPC-1) but did not bind to the NRP-negative PC-3 cell line, and binding was observed with liposomal peptide concentrations as low as 0.16mol%. Binding of the C-LPP liposomes was receptor-limited, with saturation observed at high liposome concentrations. The identical peptide sequence bearing an amide terminus did not bind specifically, accumulating only with a high (2.5mol%) peptide concentration and adhering equally to NRP positive and negative cell lines. The binding of C-LPP liposomes conjugated with 0.63mol% of the peptide was 83-fold greater than liposomes conjugated with the amide version of the peptide. Cellular internalization was also enhanced with C-LPP liposomes, with 80% internalized following 3h incubation. Additionally, fluorescence in the blood pool (~40% of the injected dose) was similar for liposomes conjugated with 0.63mol% of carboxyl-terminated peptide and non-targeted liposomes at 24h after injection, indicating stable circulation. Prior to doxorubicin treatment, in vivo tumor accumulation and vascular targeting were increased for peptide-conjugated liposomes compared to non-targeted liposomes based on confocal imaging of a fluorescent cargo, and the availability of the vascular receptor was confirmed with ultrasound molecular imaging. Finally, over a 4-week course of therapy, tumor knockdown resulting from doxorubicin-loaded, C-LPP liposomes was similar to non-targeted liposomes in syngeneic tumor-bearing FVB mice and C-LPP liposomes reduced doxorubicin accumulation in the skin and heart and eliminated skin toxicity. Taken together, our results demonstrate that a carboxyl-terminated RXXR peptide sequence, conjugated to liposomes at a concentration of 0.63mol%, retains long circulation but enhances binding and internalization, and reduces toxicity.

Safe and efficient gene therapy for the treatment of Duchenne muscular dystrophy (DMD), a genetic disorder, is required. For this, the muscle-targeting delivery system of genes and nucleic acids is ideal. In this study, we focused on the A2G80 peptide, which has an affinity for α-dystroglycan expressed on muscle cell membranes, as a muscle targeted nanocarrier for DMD and developed A2G80-modified liposomes. We also prepared A2G80-modified liposomes coated with long- and short-chain PEG, called A2G80-LSP-Lip, to improve the blood circulation of liposomes using microfluidics. The liposomes had a particle size of approximately 80 nm. A2G80-LSP-Lip showed an affinity for the muscle tissue section of mice by overlay assay. When the liposomes were administered to DMD model mice (mdx mice) via the tail vein, A2G80-LSP-Lip accumulated efficiently in muscle tissue compared to control liposomes. These results suggest that A2G80-LSP-Lip can function as a muscle-targeting liposome for DMD via systemic administration, and may be a useful tool for DMD treatment. Unlabelled Image [ABSTRACT FROM AUTHOR]

Development of liposomal nanomedicine with robust stability, high drug loading and synergistic efficacy is a promising strategy for effective cancer therapy. Here, we present an iron-crosslinked rosmarinic liposome (Rososome) which can load high contents of drugs (including 25.8% rosmarinic acid and 9.04% doxorubicin), keep stable in a high concentration of anionic detergent and exhibit synergistic anti-cancer efficacy. The Rososomes were constructed by rosmarinic acid-lipid conjugates which not only work synergistically with doxorubicin by producing reactive oxygen species but also provide catechol moieties for the iron cross-linkages. The cross-linkages can lock the payloads tightly, endowing the crosslinked Rososome with better stability and pharmacokinetics than its non-crosslinked counterpart. On the syngeneic mouse model of breast cancer, the iron-crosslinked Rososomes exhibit better anticancer efficacy than free rosmarinic acid, doxorubicin, non-crosslinked Rososome and commercial liposomal formulation of doxorubicin (DOXIL). This study introduces a novel strategy for the development of liposomes with robust stability, high drug loading and synergistic anti-cancer efficacy. Unlabelled Image [ABSTRACT FROM AUTHOR]

Clinically efficacious medication in anticancer therapy has been successfully designed with liposome-based nanomedicine. The liposomal formulation in cancer drug delivery can be facilitated with a functionalized peptide that mediates the specific drug delivery opportunities with increased drug penetrability, specific accumulation in the targeted site, and enhanced therapeutic efficacy. This review aims to focus on recent advances in peptide-functionalized liposomal formulation techniques in cancer diagnosis and treatment regarding recently published literature. It also will highlight different aspects of novel liposomal formulation techniques that incorporate surface functionalization with peptides for better anticancer effect and current challenges in peptide-functionalized liposomal drug formulation. Unlabelled Image • Liposome surfaces can be functionalized for target-mediated cancer therapy. • Surface-functionalized liposomes with peptides enhance therapeutic efficacy. • Peptide-functionalized liposomes can be tagged with imaging agents for cancer diagnostic. • Large scale production and storage of liposomes is still challenging [ABSTRACT FROM AUTHOR]

Bone marrow (BM) is the central immunological organ and the origin of hematological diseases. Efficient and specific drug delivery to the BM is an unmet need. We tested delivery of fluorescent indocarbocyanine lipids (ICLs, DiR, DiD, DiI) as a model lipophilic cargo, via different carriers. Systemically injected T-lymphocyte cell line Jurkat delivered ICLs to the BM more efficiently than erythrocytes, and more selectively than PEGylated liposomes. Near infrared imaging showed that the delivery was restricted to the BM, lungs, liver and spleen, with no accumulation in the kidneys, brain, heart, intestines, fat tissue and pancreas. Following systemic injection of ICL-labeled cells in immunodeficient or immunocompetent mice, few cells arrived in the BM intact. However, between 5 and 10% of BM cells were ICL-positive. Confocal microscopy of intact BM confirmed that ICLs are delivered independently of the injected cells. Flow cytometry analysis showed that the lipid accumulated in both CD11b + and CD11b- cells, and in hematopoietic progenitors. In a xenograft model of acute myeloid leukemia, a single injection of 10 million Jurkat cells delivered DiD to ~15% of the tumor cells. ICL-labeled cells disappeared from blood almost immediately post-intravenous injection, but numerous cell-derived microparticles continued to circulate in blood. The microparticle particle formation was not due to the ICL labeling or complement attack and was observed after injection of both syngeneic and xenogeneic cells. Injection of microparticles produced in vitro from Jurkat cells resulted in a similar ICL delivery as the injection of intact Jurkat cells. Our results demonstrate a novel delivery paradigm wherein systemically injected cells release microparticles that accumulate in the BM. In addition, the results have important implications for studies involving systemically administered cell therapies. Unlabelled Image • Cells delivered a lipid payload (indocarbocyanine lipid DiR) to bone marrow more efficiently than erythrocytes and more selectively than liposomes • The lipid payload was delivered to the bone marrow independently of the injected cells • The lipid payload was delivered to the bone marrow via microparticles released in vivo • The phenomenon was independent of the immune system of the host and was observed for syngeneic and xenogeneic cells • In vitro preformed microparticles efficiently delivered the lipid payload to the bone marrow [ABSTRACT FROM AUTHOR]

Despite the progress made with the recent clinical use of the anticancer compound cabazitaxel, the efficacy in patients remains unsatisfactory, largely due to the high in vivo toxicity of the agent. Therefore, strategies that achieve favorable outcomes and good safety profiles will greatly expand the repertoire of this potent agent. Here, we propose a combinatorial strategy to reform the cabazitaxel agent and the use of sequential supramolecular nanoassembly with liposomal compositions to assemble a prodrug-formulated liposome, termed lipoprodrug, for safe and effective drug delivery. Reconstructing cabazitaxel with a polyunsaturated fatty acid (i.e. , docosahexaenoic acid) via a hydrolyzable ester bond confers the generated prodrug with the ability to be readily integrated into the lipid bilayer of liposomes for systemic administration. The resulting lipoprodrug scaffold showed significantly sustained drug release profiles and improved pharmacokinetics in rats as well as a reduction in systemic toxicity in vivo. Notably, the lipoprodrug outperformed free cabazitaxel in terms of in vivo therapeutic efficacy in multiple separate tumor xenograft-bearing mouse models, one of which was a patient-derived xenograft model. Surprisingly, the lipoprodrug was able to reduce tumor invasiveness and reprogram the tumor immunosuppressive microenvironment by proinflammatory macrophage polarization. Our findings validate this lipoprodrug approach as a simple yet effective strategy for transforming the highly toxic cabazitaxel agent into an efficacious nanomedicine with excellent in vivo tolerability. This approach could also be applied to rescue other drugs or drug candidates that have failed in clinical trials due to poor pharmacokinetic properties or unacceptable toxicity in patients. Image 1 • PUFAylation of anticancer cabazitaxel drug facilitated the incorporation of the drug into liposomal formulation. • The liposomal prodrug (termed lipoprodrug) was established for the drug optimization. • Lipoprodrug scaffold showed sustained drug release profiles in vitro and improved pharmacokinetics in vivo. • Lipoprodrug potentiated the efficacy of cabazitaxel in multiple mice models, including a patient-derived xenograft model. • Lipoprodrug remarkably alleviated the toxicity with a high safety margin relative to cabazitaxel in animals. [ABSTRACT FROM AUTHOR]