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Targeted delivery of anti-inflammatory drugs to macrophages has attracted great attention for selectively alleviating the symptoms of ulcerative colitis (UC), while minimizing adverse effects. Herein, we aimed to compare the in vivo pharmacokinetics and therapeutic outcomes of macrophage-targeted nanoparticles (NPs) via oral administration and intravenous injection. Polymeric NPs were employed to load an anti-inflammatory drug (curcumin, CUR), followed by surface functionalization with hyaluronic acid (HA). The resulting HA-CUR-NPs had an average diameter of 281 nm and a negatively charged surface. These NPs showed excellent biocompatibility and a significantly higher cell internalization efficiency in RAW 264.7 macrophages compared with their counterparts (carboxymethyl cellulose-functionalized CUR-encapsulated NPs, CUL-CUR-NPs). Moreover, HA-CUR-NPs exhibited a dramatically stronger capacity to inhibit the mRNA expression levels of the typical pro-inflammatory cytokines from lipopolysaccharide-stimulated macrophages compared with CUL-CUR-NPs. In vivo experiments revealed that HA-CUR-NPs after i.v. injection could improve the pharmacokinetics of CUR, and that it showed much better UC therapeutic outcomes compared with the oral administration way. Collectively, in comparison with HA-CUR-NPs (oral), HA-CUR-NPs (i.v.) possess a higher CUR delivery efficiency to the colitis mucosa, which can be developed as an efficient platform for UC treatment.

The therapeutic efficacy of oral nanotherapeutics against colorectal cancer (CRC) is restricted by inadequate drug accumulation, immunosuppressive microenvironment, and intestinal microbiota imbalance. To overcome these challenges, we elaborately constructed 6-gingerol (Gin)-loaded magnetic mesoporous silicon nanoparticles and functionalized their surface with mulberry leaf-extracted lipids (MLLs) and Pluronic F127 (P 127 ). In vitro experiments revealed that P 127 functionalization and alternating magnetic fields (AMFs) promoted internalization of the obtained P 127 -MLL@Gins by colorectal tumor cells and induced their apoptosis/ferroptosis through Gin/ferrous ion-induced oxidative stress and magneto-thermal effect. After oral administration, P 127 -MLL@Gins safely passed to the colorectal lumen, infiltrated the mucus barrier, and penetrated into the deep tumors under the influence of AMFs. Subsequently, the P 127 -MLL@Gin (+ AMF) treatment activated antitumor immunity and suppressed tumor growth. We also found that this therapeutic modality significantly increased the abundance of beneficial bacteria (e.g., Bacillus and unclassified-c-Bacilli), reduced the proportions of harmful bacteria (e.g., Bacteroides and Alloprevotella), and increased lipid oxidation metabolites. Strikingly, checkpoint blockers synergistically improved the therapeutic outcomes of P 127 -MLL@Gins (+ AMF) against orthotopic and distant colorectal tumors and significantly prolonged mouse life spans. Overall, this oral therapeutic platform is a promising modality for synergistic treatment of CRC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Oral treatment of colon diseases with the CRISPR/Cas9 system has been hampered by the lack of a safe and efficient delivery platform. Overexpressed CD98 plays a crucial role in the progression of ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC). In this study, lipid nanoparticles (LNPs) derived from mulberry leaves are functionalized with Pluronic copolymers and optimized to deliver the CRISPR/Cas gene editing machinery for CD98 knockdown. The obtained LNPs possessed a hydrodynamic diameter of 267.2 nm, a narrow size distribution, and a negative surface charge (-25.6 mV). Incorporating Pluronic F127 into LNPs improved their stability in the gastrointestinal tract and facilitated their penetration through the colonic mucus barrier. The galactose end groups promoted endocytosis of the LNPs by macrophages via asialoglycoprotein receptor-mediated endocytosis, with a transfection efficiency of 2.2-fold higher than Lipofectamine 6000. The LNPs significantly decreased CD98 expression, down-regulated pro-inflammatory cytokines (TNF-α and IL-6), up-regulated anti-inflammatory factors (IL-10), and polarized macrophages to M2 phenotype. Oral administration of LNPs mitigated UC and CAC by alleviating inflammation, restoring the colonic barrier, and modulating intestinal microbiota. As the first oral CRISPR/Cas9 delivery LNP, this system offers a precise and efficient platform for the oral treatment of colon diseases., (© 2024 Wiley‐VCH GmbH.)

Designing targeted drug delivery systems to effectively treat bone diseases ranging from osteoporosis to nonunion bone defects remains a significant challenge. Previously, nanoparticles (NPs) self-assembled from diblock copolymers of poly(styrene- alt -maleic anhydride)- b -poly(styrene) (PSMA- b -PS) delivering a Wnt agonist were shown to effectively target bone and improve healing via the introduction of a peptide with high affinity to tartrate-resistant acid phosphatase (TRAP), an enzyme deposited by the osteoclasts during bone remodeling. Despite these promising results, the underlying biological factors governing targeting and subsequent drug delivery system (DDS) design parameters have not been examined to enable the rational design to improve bone selectivity. Therefore, this work investigated the effect of target ligand density, the treatment window after injury, specificity of TRAP binding peptide (TBP), the extent of TRAP deposition, and underlying genetic factors (e.g., mouse strain differences) on TBP-NP targeting. Data based on in vitro binding studies and in vivo biodistribution analyses using a murine femoral fracture model suggest that TBP-NP-TRAP interactions and TBP-NP bone accumulation were ligand-density-dependent; in vitro, TRAP affinity was correlated with ligand density up to the maximum of 200,000 TBP ligands/NP, while NPs with 80,000 TBP ligands showed 2-fold increase in fracture accumulation at day 21 post injury compared with that of untargeted or scrambled controls. While fracture accumulation exhibited similar trends when injected at day 3 compared to that at day 21 postfracture, there were no significant differences observed between TBP-functionalized and control NPs, possibly due to saturation of TRAP by NPs at day 3. Leveraging a calcium-depletion diet, TRAP deposition and TBP-NP bone accumulation were positively correlated, confirming that TRAP-TBP binding leads to TBP-NP bone accumulation in vivo. Furthermore, TBP-NP exhibited similar bone accumulation in both C57BL/6 and BALB/c mouse strains versus control NPs, suggesting the broad applicability of TBP-NP regardless of the underlying genetic differences. These studies provide insight into TBP-NP design, mechanism, and therapeutic windows, which inform NP design and treatment strategies for fractures and other bone-associated diseases that leverage TRAP, such as marrow-related hematologic diseases.

The treatment outcomes of oral medications against ulcerative colitis (UC) have long been restricted by low drug accumulation in the colitis mucosa and subsequent unsatisfactory therapeutic efficacy. Here, high-performance pluronic F127 (P127)-modified gold shell (AuS)-polymeric core nanotherapeutics loading with curcumin (CUR) is constructed. Under near-infrared irradiation, the resultant P127-AuS@CURs generate transient mild photothermia (TMP; ≈42 °C, 10 min), which facilitates their penetration through colonic mucus and favors multiple cellular processes, including cell internalization, lysosomal escape, and controlled CUR release. This strategy relieves intracellular oxidative stress, improves wound healing, and reduces immune responses by polarizing the proinflammatory M1-type macrophages to the anti-inflammatory M2-type. Upon oral administration of hydrogel-encapsulating P127-AuS@CURs plus intestinal intralumen TMP, their therapeutic effects against acute and chronic UC are demonstrated to be superior to those of a widely used clinical drug, dexamethasone. The treatment of P127-AuS@CURs (+ TMP) elevates the proportions of beneficial bacteria (e.g., Lactobacillus and Lachnospiraceae), whose metabolites can also mitigate colitis symptoms by regulating genes associated with antioxidation, anti-inflammation, and wound healing. Overall, the intestinal intralumen TMP offers a promising approach to enhance the therapeutic outcomes of noninvasive medicines against UC., (© 2024 Wiley‐VCH GmbH.)

Fracture healing is a complex interplay of molecular and cellular mechanisms lasting from days to weeks. The inflammatory phase is the first stage of fracture healing and is critical in setting the stage for successful healing. There has been growing interest in exploring the role of the immune system and novel therapeutic strategies, such as nanoparticle drug delivery systems in enhancing fracture healing. Advancements in nanotechnology have revolutionized drug delivery systems to the extent that they can modulate immune response during fracture healing by leveraging unique physiochemical properties. Therefore, understanding the intricate interactions between nanoparticle-based drug delivery systems and the immune response, specifically macrophages, is essential for therapeutic efficacy. This review provides a comprehensive overview of the relationship between the immune system and nanoparticles during fracture healing. Specifically, we highlight the influence of nanoparticle characteristics, such as size, surface properties, and composition, on macrophage activation, polarization, and subsequent immune responses. IMPACT STATEMENT: This review provides valuable insights into the interplay between fracture healing, the immune system, and nanoparticle-based drug delivery systems. Understanding nanoparticle-macrophage interactions can advance the development of innovative therapeutic approaches to enhance fracture healing, improve patient outcomes, and pave the way for advancements in regenerative medicine., Competing Interests: Declaration of competing interest No competing financial interests exist., (Copyright © 2023. Published by Elsevier Inc.)

Oral administration is the most preferred approach for treating colon diseases, and in situ vaccination has emerged as a promising cancer therapeutic strategy. However, the lack of effective drug delivery platforms hampered the application of in situ vaccination strategy in oral treatment of colorectal cancer (CRC). Here, we construct an oral core-shell nanomedicine by preparing a silk fibroin-based dual sonosensitizer (chlorin e6, Ce6)- and immunoadjuvant (imiquimod, R837)-loaded nanoparticle as the core, with its surface coated with plant-extracted lipids and pluronic F127 (p 127 ). The resultant nanomedicines (Ce6/R837@Lp 127 NPs) maintain stability during their passage through the gastrointestinal tract and exert improved locomotor activities under ultrasound irradiation, achieving efficient colonic mucus infiltration and specific tumor penetration. Thereafter, Ce6/R837@Lp 127 NPs induce immunogenic death of colorectal tumor cells by sonodynamic treatment, and the generated neoantigens in the presence of R837 serve as a potent in situ vaccine. By integrating with immune checkpoint blockades, the combined treatment modality inhibits orthotopic tumors, eradicates distant tumors, and modulates intestinal microbiota. As the first oral in situ vaccination, this work spotlights a robust oral nanoplatform for producing a personalized vaccine against CRC.

The clinical application of conventional medications for hepatocellular carcinoma treatment has been severely restricted by their adverse effects and unsatisfactory therapeutic effectiveness. Inspired by the concept of 'medicine food homology', we extracted and purified natural exosome-like lipid nanoparticles (LNPs) from black mulberry (Morus nigra L.) leaves. The obtained MLNPs possessed a desirable hydrodynamic particle size (162.1 nm), a uniform size distribution (polydispersity index = 0.025), and a negative surface charge (-26.6 mv). These natural LNPs were rich in glycolipids, functional proteins, and active small molecules (e.g., rutin and quercetin 3-O-glucoside). In vitro experiments revealed that MLNPs were preferentially internalized by liver tumor cell lines via galactose receptor-mediated endocytosis, increased intracellular oxidative stress, and triggered mitochondrial damage, resulting in suppressing the viability, migration, and invasion of these cells. Importantly, in vivo investigations suggested that oral MLNPs entered into the circulatory system mainly through the jejunum and colon, and they exhibited negligible adverse effects and superior anti-liver tumor outcomes through direct tumor killing and intestinal microbiota modulation. These findings collectively demonstrate the potential of MLNPs as a natural, safe, and robust nanomedicine for oral treatment of hepatocellular carcinoma., (© 2023. The Author(s).)

The treatment efficacies of conventional medications against colorectal cancer (CRC) are restricted by a low penetrative, hypoxic, and immunosuppressive tumor microenvironment. To address these restrictions, we developed an innovative antitumor platform that employs calcium overload-phototherapy using mitochondrial N770-conjugated mesoporous silica nanoparticles loaded with CaO 2 (CaO 2 -N770@MSNs). A loading level of 14.0 wt% for CaO 2 -N770@MSNs was measured, constituting an adequate therapeutic dosage. With the combination of oxygen generated from CaO 2 and hyperthermia under near-infrared irradiation, CaO 2 -N770@MSNs penetrated through the dense mucus, accumulated in the colorectal tumor tissues, and inhibited tumor cell growth through endoplasmic reticulum stress and mitochondrial damage. The combination of calcium overload and phototherapy revealed high therapeutic efficacy against orthotopic colorectal tumors, alleviated the immunosuppressive microenvironment, elevated the abundance of beneficial microorganisms (e.g., Lactobacillaceae and Lachnospiraceae), and decreased harmful microorganisms (e.g., Bacteroidaceae and Muribaculaceae). Moreover, together with immune checkpoint blocker (αPD-L1), these nanoparticles showed an ability to eradicate both orthotopic and distant tumors, while potentiating systemic antitumor immunity. This treatment platform (CaO 2 -N770@MSNs plus αPD-L1) open a new horizon of synergistic treatment against hypoxic CRC with high killing power and safety., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: Oral administration is the most common route for treating colonic diseases that present increased incidences in recent years. Colonic mucus is a critical rate-limiting barrier for the accumulation of oral therapeutics in the colonic tissues. To overcome this obstacle, mucus-penetrating nanotherapeutics have been exploited to increase the accumulated amounts of drugs in the diseased sites and improve their treatment outcomes against colonic diseases., Areas Covered: In this review, we introduce the structure and composition of colonic mucus as well as its impact on the bioavailability of oral drugs. We also introduce various technologies used in the construction of mucus-penetrating nanomedicines (e.g. surface modification of polymers, physical means and biological strategies) and discuss their mechanisms and potential techniques for improving mucus penetration of nanotherapeutics., Expert Opinion: The mucus barrier is often overlooked in oral drug delivery. The weak mucus permeability of conventional medications greatly lowers drug bioavailability. This challenge can be addressed through physical, chemical and biological technologies. In addition to the reported methods, promising approaches may be discovered through interdisciplinary research that further helps enhance the mucus penetration of nanomedicines.

Multidrug resistance (MDR) is the main cause of clinical chemotherapy failure, and new strategies to overcome MDR are needed. We report multi-responsive silk fibroin nanoparticles (SFNs) co-loaded with the chemotherapeutic drug doxorubicin (DOX) and PX478 (a hypoxia-inducible factor inhibitor), which was functionalized with folic acid (FA). This combination could actively target tumor cells and respond to the release of PX478, inhibit the hypoxia-inducible factor (HIF) gene and its related downstream drug-resistant target genes. The FA-PX478-DOX-SFNs (F-P-D-S) combination showed accelerated drug release profiles in the media simulating the tumor microenvironment, which had acidic pH, high levels of reactive oxygen species and high levels of glutathione. Compared with PX478-DOX-SFNs (P-D-S) without targeted modification, the cellular uptake rate of F-P-D-S increased. In addition, F-P-D-S quickly achieved lysosomal escape, enabling DOX to rapidly enter the nucleus to kill the drug-resistant cells. A cytotoxicity test indicated that the IC 50 of DOX against MCF-7/ADR cells was 1.0 μg/mL in F-P-D-S, which was 26 times lower than that of free DOX (25.6 μg/mL). F-P-D-S significantly down-regulated HIF-1α, MDR1, VEGF and GLUT-1 and P-gp protein to overcome multidrug resistance. This effective synergistic chemotherapy strategy for HIF inhibition has potential for use in the treatment of multidrug-resistant tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

The therapeutic outcomes of oral nanomedicines against colon cancer are heavily compromised by their lack of specific penetration into the internal tumor, favorable anti-tumor activity, and activation of anti-tumor immunity. Herein, hydrogen peroxide (H 2 O 2 )/ultrasound (US)-driven mesoporous manganese oxide (MnO x )-based nanomotors are constructed by loading mitochondrial sonosensitizers into their mesoporous channels and orderly dual-functionalizing their surface with silk fibroin and chondroitin sulfate. The locomotory activities and tumor-targeting capacities of the resultant nanomotors (CS-ID@NMs) are greatly improved in the presence of H 2 O 2 and US irradiation, inducing efficient mucus-traversing and deep tumor penetration. The excess H 2 O 2 in the tumor microenvironment (TME) is decomposed into hydroxyl radicals and oxygen by an Mn 2+ -mediated Fenton-like reaction, and the produced oxygen participates in sonodynamic therapy (SDT), yielding abundant singlet oxygen. The combined Mn 2+ -mediated chemodynamic therapy and SDT cause effective ferropotosis of tumor cells and accelerate the release of tumor antigens. Importantly, animal experiments reveal that the treatment of combining oral hydrogel (chitosan/alginate)-embedding CS-ID@NMs and immune checkpoint inhibitors can simultaneously suppress the growth of primary and distal tumors through direct killing, reversion of immunosuppressive TME, and potentiation of systemic anti-tumor immunity, demonstrating that the CS-ID@NM-based platform is a robust oral system for synergistic treatment of colon cancer., (© 2022 Wiley-VCH GmbH.)

Oral nanoparticles have been considered a prospective drug delivery carrier against ulcerative colitis (UC). To enhance the mucus-penetrating capacity and aqueous solubility, and strengthen the anti-inflammatory effect of resveratrol (RSV), we fabricated RSV-loaded silk fibroin-based nanoparticles with the functionalization of Pluronic F127 (PF-127). The obtained PF-127-functionalized RSV-loaded NPs had an average particle size around 170 nm, a narrow size distribution (polydispersity index < 0.2), and negative zeta potential (−20.5 mV). Our results indicated that the introduction of PF-127 strengthened the mucus-penetrating property of NPs. In vitro studies suggested that NPs with PF-127 enhanced the suppression of the secretion of proinflammatory cytokine TNF-α and reactive oxygen species (ROS) from RAW 264.7 macrophages under lipopolysaccharide stimulation in comparison with other counterparts. According to the evaluation of macro symptoms and main inflammatory cytokines, we further report preferable therapeutic outcomes achieved by PF-127 functionalized-NP-treated dextran sulphate sodium (DSS) groups in the colitis model compared with blank silk fibroin NPs and RSV-loaded NPs without the functionalization of PF-127. Taken together, this work suggests that the fabricated PF-127 NPs via the oral route are promising and useful RSV-loaded nanocarriers for UC treatment.

Phototherapy is an important strategy to inhibit tumor growth and activate antitumor immunity. However, the effect of photothermal/photodynamic therapy (PTT/PDT) is restricted by limited tumor penetration depth and unsatisfactory potentiation of antitumor immunity. Here, a near-infrared (NIR)-driven nanomotor is constructed with a mesoporous silicon nanoparticle (MSN) as the core, end-capped with Antheraea pernyi silk fibroin (ApSF) comprising arginine-glycine-aspartate (RGD) tripeptides. Upon NIR irradiation, the resulting ApSF-coated MSNs (DIMs) loading with photosensitizers (ICG derivatives, IDs) and chemotherapeutic drugs (doxorubicin, Dox) can efficiently penetrate into the internal tumor tissues and achieve effective phototherapy. Combined with chemotherapy, a triple-modal treatment (PTT, PDT, and chemotherapy) approach is developed to induce the immunogenic cell death of tumor cells and to accelerate the release of damage-associated molecular patterns. In vivo results suggest that DIMs can promote the maturation of dendritic cells and surge the number of infiltrated immune cells. Meanwhile, DIMs can polarize macrophages from M2 to M1 phenotypes and reduce the percentages of immunosuppressive Tregs, which reverse the immunosuppressive tumor microenvironment and activate systemic antitumor immunity. By achieving synergistic effects on the tumor inhibition and the antitumor immunity activation, DIMs show great promise as new nanoplatforms to treat metastatic breast cancer., (© 2022 Wiley-VCH GmbH.)

Introduction: High drug delivery efficiency, desirable therapeutic effects, and low toxicity have become crucial to develop nanotherapeutics. Natural nanoparticles (NPs) from edible plants contain a large quantity of bioactive small molecules, proteins, glycolipids, and microRNAs. The development of these NPs has rapidly attracted increasing attention due to their merits of green production, excellent biocompatibility, anti-inflammatory activities, and antitumor capacities., Areas Covered: Here, we introduce the extraction, purification, and construction strategies of plant-derived exosome-like NPs (PDENs) and expound on their physicochemical properties, biomedical functions, and therapeutic effects against various diseases. We also recapitulate future directions and challenges of the emerging nanotherapeutics., Expert Opinion: PDENs have been used as natural nanotherapeutics and nanocarriers. The challenges of applying PDENs primarily stem from the lack of understanding of the mechanisms that drive the tissue-specific targeting properties. Elucidating the underlying targeting mechanisms is one of the major focuses in this review, which helps to gain new research opportunities for the development of natural nanotherapeutics. Despite excellent biosafety and therapeutic effects in the treatment of various diseases, the medical translation of these NPs has still been limited by low yields and cold-chain dependence. Therefore, exploiting new techniques will be required for their massive production and storage.

Ulcerative colitis (UC) with its rapidly increasing incidence has become an emerging challenge for public health. Therapeutic agents are required to be specifically delivered to colon epithelial cells and macrophages with controlled release in the cytoplasm for wound healing, inflammation alleviation, and microbiota rebalance. As a promising biomaterial for accomplishing this, Antheraea pernyi silk fibroin (ApSF) was selected and engineered to form nanoparticles (NPs) loaded with the anti-inflammatory drug, resveratrol (Res). The intrinsic features of these fabricated Res-ApNPs included targeting of colonic epithelial cells and macrophages, lysosomal escape capacity, and responsiveness to pH, reactive oxygen species (ROS), and glutathione, which were pertinent to their functional units such as arginine-glycine-aspartate tripeptides, α-helixes, β-sheets, and disulfide bonds, enabling on-demand release of Res molecules in the cytoplasm of target cells. The Res-ApNP treatment restored damaged colonic epithelial barriers, polarized macrophages to type M2, alleviated inflammatory reactions, and reduced the level of intracellular ROS. Oral treatment with chitosan-alginate hydrogels embedded with Res-ApNPs substantially relieved UC symptoms, as evidenced by decreased colonic inflammation, increased synthesis of tight-junction proteins, and rebalanced intestinal microbiota. Our findings suggest that these high-performance ApSF-based NPs can be developed as effective drug carriers for oral UC treatment., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Despite efforts to achieve tissue selectivity, the majority of systemically administered drug delivery systems (DDSs) are cleared by the mononuclear phagocyte system (MPS) before reaching target tissues regardless of disease or injury pathology. Previously, we showed that while tartrate-resistant acid phosphatase (TRAP) binding peptide (TBP)-targeted polymeric nanoparticles (TBP-NP) delivering a bone regenerative Wnt agonist improved NP fracture accumulation and expedited healing compared with controls, there was also significant MPS accumulation. Here we show that TBP-NPs are taken up by liver, spleen, lung, and bone marrow macrophages (Mϕ), with 76 ± 4%, 49 ± 11%, 27 ± 9%, and 92 ± 5% of tissue-specific Mϕ positive for NP, respectively. Clodronate liposomes (CLO) significantly depleted liver and spleen Mϕ, resulting in 1.8-fold and 3-fold lower liver and spleen and 1.3-fold and 1.6-fold greater fracture and naïve femur accumulation of TBP-NP. Interestingly, depletion and saturation of MPS using 10-fold greater TBP-NP doses also resulted in significantly higher TBP-NP accumulation at lungs and kidneys, potentially through compensatory clearance mechanisms. The higher NP dose resulted in greater TBP-NP accumulation at naïve bone tissue; however, other MPS tissues (i.e., heart and lungs) exhibited greater TBP-NP accumulation, suggesting uptake by other cell types. Most importantly, neither Mϕ depletion nor saturation strategies improved fracture site selectivity of TBP-NPs, possibly due to a reduction of Mϕ-derived osteoclasts, which deposit the TRAP epitope. Altogether, these data support that MPS-mediated clearance is a key obstacle in robust and selective fracture accumulation for systemically administered bone-targeted DDS and motivates the development of more sophisticated approaches to further improve fracture selectivity of DDS., (© 2021 Wiley Periodicals LLC.)

Tumor-selective drug delivery could enhance anticancer efficacy and avoid drug side effects. However, because of tumor heterogeneity, current nanoparticle-based drug delivery systems rarely improve clinical outcomes significantly, commonly only reducing systemic toxicity. In this work, a new tumor-specific, tyrosinase-responsive cascade amplification release nanoparticle (TR-CARN) was developed to fulfill the needs for tumor-specific drug delivery and high efficacy cancer treatment. Tyrosinase (Tyr) is specifically expressed in melanomas and can catalyze acetaminophen (APAP) to increase reactive oxygen species (ROS). It was therefore utilized here to initiate the ROS amplification procedure. In TR-CARN, a ROS-responsive prodrug BDOX was loaded into an amphiphilic polymer, and APAP was linked to the polymer through a ROS-cleavable thioether bond. TR-CARN caused reduced side effects during the delivery because of the low toxicity of BDOX. Once TR-CARN entered into the tumor, endogenous ROS triggered initial APAP and BDOX release. Tyr-mediated ROS synthesis by APAP then accelerated APAP and BDOX release and toxification. Consequently, TR-CARN achieved melanoma-specific treatment of high efficacy through the cascade amplification strategy with enhanced biosafety.

The incidence of inflammatory bowel disease (IBD) is rapidly rising throughout the world. Although tremendous efforts have been made, limited therapeutics are available for IBD management. Natural active small molecules (NASMs), which are a gift of nature to humanity, have been widely used in the prevention and alleviation of IBD; they have numerous advantageous features, including excellent biocompatibility, pharmacological activity, and mass production potential. Oral route is the most common and acceptable approach for drug administration, but the clinical application of NASMs in IBD treatment via oral route has been seriously restricted by their inherent limitations such as high hydrophobicity, instability, and poor bioavailability. With the development of nanotechnology, polymeric nanoparticles (NPs) have provided a promising platform that can efficiently encapsulate versatile NASMs, overcome multiple drug delivery barriers, and orally deliver the loaded NASMs to targeted tissues or cells while enhancing their stability and bioavailability. Thus, NPs can enhance the preventive and therapeutic effects of NASMs against IBD. Herein, we summarize the recent knowledge about polymeric matrix-based carriers, targeting ligands for drug delivery, and NASMs. We also discuss the current challenges and future developmental directions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Theranostic nanoparticles (NPs) have emerged as promising candidates for cancer diagnosis and treatment. Manganese dioxide (MnO 2 )-based NPs are potential contrast agents with excellent paramagnetic property and biocompatibility, exhibiting satisfactory magnetic resonance imaging (MRI) effects and biological safety. Recently, hyaluronic acid (HA) has gained increasing interest due to its tumor-targeting ability, which can improve the tumor affinity of manganese dioxide (MnO 2 )-based NPs. In this study, HA-coated and albumin (BSA)-templated MnO 2 and polydopamine hybrid nanoparticles (HMDNs) with tumor-targeting and superior imaging capability were fabricated via modifying the nanoparticles prepared by integrating dopamine polymerization and MnO 2 biomineralization. The modification was found to enhance the cellular uptake of HMDNs by cancer cells. The prepared HMDN had high MRI contrasting capability with a longitudinal relaxivity of 22.2 mM -1 s -1 and strong photothermal therapy (PTT) effects with nearly complete tumor ablation under laser irradiation in vivo. HMDNs also showed effective clearance through kidneys, with no toxicity to important tissues. Therefore, HMDNs with superior imaging and PTT capability presented a new method to prepare tumor-targeting multifunctional nanotheranostics.

The synergism of combination chemotherapy can only be achieved under specific drug ratios. Herein, hyaluronic acid (HA)-functionalized regenerated silk fibroin-based nanoparticles (NPs) were used to concurrently deliver curcumin (CUR) and 5-fluorouracil (5-FU) at various weight ratios (3.3 : 1, 1.6 : 1, 1.1 : 1, 1 : 1, and 1 : 1.2) to breast tumor cells. The generated HA-CUR/5-FU-NPs were found to have desirable particle sizes (around 200 nm), narrow size distributions, and negative zeta potentials (about -26.0 mV). Interestingly, these NPs showed accelerated drug release rates when they were exposed to buffers that mimicked the multi-hallmarks in the tumor microenvironment (pH/hydrogen peroxide/glutathione/hyaluronidase). The surface functionalization of NPs with HA endowed them with in vitro and in vivo breast tumor-targeting properties. Furthermore, we found that the co-loading of CUR and 5-FU in HA-functionalized NPs exhibited obvious synergistic anti-cancer, pro-apoptotic, and anti-migration effects, and the strongest synergism was found at the CUR/5-FU weight ratio of 1 : 1.2. Most importantly, mice experiments revealed that HA-CUR/5-FU-NPs (1 : 1.2) showed a superior anti-cancer activity against metastatic breast cancer compared to the single drug-loaded NPs and non-functionalized CUR/5-FU-NPs (1 : 1.2). Collectively, these results demonstrate that HA-CUR/5-FU-NPs (1 : 1.2) can be exploited as a robust nanococktail for the treatment of breast cancer and its lung metastasis.

Liver metastasis (LM) occurs in various cancers, and its early and accurate diagnosis is of great importance. However, the detection of small LMs is still a great challenge because of the subtle differences between normal liver tissue and small metastases. Herein, we prepare glutathione (GSH)-responsive hyaluronic acid-coated iron oxide nanoparticles (HIONPs) for highly sensitive diagnosis of LMs through a facile one-pot method. HIONPs greatly enhance the signal of MRI in tumor metastases as T 1 contrast agent (CA), whereas they substantially decrease the signal of liver as T 2 CA as they aggregate into clusters upon the high GSH in liver. Consequently, MRI contrasted by HIONPs clearly distinguishes metastatic tumors (bright) from surrounding liver tissues (dark). HIONPs with superior LM contrasting capability and facile synthesis are very promising for clinical translation and indicate a new strategy to develop an ultrasensitive MRI CA for LM diagnosis that exploits high GSH level in the liver.

The therapeutic efficacies of oral nanotherapeutics for ulcerative colitis (UC) are seriously hindered by the lack of mucus-penetrating capacity and uncontrolled drug release. To overcome these limitations, the surface of poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) was functionalized with pluronic F127 (PF127), and catalase (CAT)/curcumin (CUR) was co-encapsulated into these NPs. The obtained P-CUR/CAT-NPs had a hydrodynamic particle size of approximately 274.1 nm, narrow size distribution, negative zeta potential (-14.0 mV), and smooth surface morphology. Moreover, the introduction of PF127 to the surface of NPs not only facilitated their mucus penetration, but also improved their cellular uptake efficiency by the target cells (macrophages). We further found that the encapsulation of CAT could remarkably increase the release rate of CUR from NPs in the presence of an H 2 O 2 -rich environment. Additionally, P-CUR/CAT-NPs showed the strongest capacity to suppress the secretion of the main pro-inflammatory cytokines, in comparison with their counterparts (CUR-NPs and P-CUR-NPs). Importantly, oral administration of P-CAT/CUR-NPs showed the best therapeutic outcomes than the other NPs. Collectively, these results clearly demonstrate that these mucus-penetrating NPs loaded with CAT and CUR can be exploited as an efficient nanotherapeutic for UC therapy.

Lung metastasis of breast cancer is a leading cause of cancer-related death in women. Herein, we attempted to simultaneously inhibit the growth and lung metastasis of breast cancer by delivering quercetin (QU) using LyP-1-functionalized regenerated silk fibroin-based nanoparticles (NPs). The generated LyP-1-QU-NPs had a desirable diameter (203.2 nm) and a negatively charged surface (-12.7 mV). Interestingly, these NPs exhibited intrinsic responsibilities when triggered by various stimulating factors in the tumor microenvironment (acidic pH, reactive oxygen species, and glutathione). In vitro experiments revealed that the introduction of LyP-1 to the NP surface could significantly increase their cellular uptake efficiencies by 4 T1 cells, and facilitate their accumulation in mitochondria. Moreover, LyP-1-QU-NPs showed the strongest mitochondrial damage effect among all the treatment groups. We also found that LyP-1-QU-NPs not only exhibited excellent pro-apoptotic activities but also presented strong inhibitory effects on cell mobility (migration and invasion) through anti-glycolysis and pro-autophagy. Mice experiments confirmed that LyP-1-QU-NPs could efficiently inhibit the in situ growth of breast tumors and further restrict their lung metastasis. Collectively, our results demonstrate that LyP-1-QU-NPs, which integrates the functions of tumor cell targeting, mitochondria targeting, bioresponsive drug release, pro-apoptosis, and anti-mobility, can be developed as a promising nanotherapeutic for the effective treatment of breast cancer and its lung metastasis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The integration of multimodal functions into one nanoplatform holds great promise for enhancing anticancer drug action and mitigating adverse effects. Herein, we prepared hyaluronic acid-functionalized regenerated silk fibroin-based nanoparticles (NPs) loading with photosensitizer (NIR770) and doxorubicin (DOX). The resultant HNDNPs had a desirable diameter of 161.0 nm and a negative zeta-potential of -30.5 mV. Interestingly, they showed excellent responses when triggered with various stimuli (acidity, reactive oxygen species, glutathione, hyaluronidase, or hyperthermia). Cell experiments revealed that HNDNPs could be specifically internalized by A549 cells, and efficiently released the payloads into the cytoplasm. Moreover, NIR770 was preferentially retained in mitochondria due to its lipophilic and cationic properties, which exhibited highly efficient photothermal therapy and photodynamic therapy upon near infrared (NIR) irradiation. Meanwhile, DOX molecules were mainly accumulated in the nucleus. Intravenous injection of HNDNPs into mice followed by NIR irradiation provided excellent multimodal imaging (NIR, photothermal, and photoacoustic imaging), almost eliminated the entire tumor, and greatly prolonged mice survival time with no side effects. Our study demonstrates that this HNDNP, which integrates the functions of tumor targeting, on-demand drug release, multimodal imaging, mitochondrial phototherapy, and chemotherapy, can be exploited as a promising nanococktail for imaging-guided synergistic treatment of cancer., (Copyright © 2020. Published by Elsevier B.V.)

Oxidative stress is associated with many acute and chronic inflammatory diseases, yet limited treatment is currently available clinically. The development of enzyme-mimicking nanomaterials (nanozymes) with good reactive oxygen species (ROS) scavenging ability and biocompatibility is a promising way for the treatment of ROS-related inflammation. Herein we report a simple and efficient one-step development of ultrasmall Cu 5.4 O nanoparticles (Cu 5.4 O USNPs) with multiple enzyme-mimicking and broad-spectrum ROS scavenging ability for the treatment of ROS-related diseases. Cu 5.4 O USNPs simultaneously possessing catalase-, superoxide dismutase-, and glutathione peroxidase-mimicking enzyme properties exhibit cytoprotective effects against ROS-mediated damage at extremely low dosage and significantly improve treatment outcomes in acute kidney injury, acute liver injury and wound healing. Meanwhile, the ultrasmall size of Cu 5.4 O USNPs enables rapid renal clearance of the nanomaterial, guaranteeing the biocompatibility. The protective effect and good biocompatibility of Cu 5.4 O USNPs will facilitate clinical treatment of ROS-related diseases and enable the development of next-generation nanozymes.

Edible plant-derived nanoparticles (NPs) have attracted increasing attention in the treatment of ulcerative colitis (UC). Lycium barbarum (LB), a popular functional fruit, possesses various biological functions. Here, fat-soluble contents were extracted from LB and further processed into LB lipid-derived NPs (LBLNs). The resultant NPs had an average hydrodynamic diameter around 189.2 nm, narrow size distribution (polydispersity index = 0.2), and negative surface charge (-34.9 mV). Moreover, they could be efficiently taken up by UC therapy-related target cells (macrophages), and over 69.0 % of macrophages internalized LBLNs after 4 h co-incubation. We further found from the in vitro results that LBLNs had strong capacities to inhibit the secretion of the main pro-inflammatory cytokines (TNF-α and IL-12) and up-regulate the expression of the typical anti-inflammatory factor (IL-10). Finally, mice experiments confirmed that LBLNs after oral administration could specifically accumulate into inflamed colon tissues, and further attenuate UC-relevant symptoms (e.g., bodyweight loss, colon shortening, increase of spleen weight, and histopathological appearance, as well as ulceration). Collectively, this study demonstrates the excellent therapeutic outcomes of LBLNs against UC and provides a promising edible nanotherapeutic for UC treatment., Competing Interests: Declaration Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

To elucidate the impacts of particle size on the cell internalization and anti-inflammatory activity of oral nanotherapeutics, curcumin (CUR)-loaded polymeric nanoparticles (NPs) with different particle sizes were fabricated. The obtained NPs with particle sizes (185-884 nm) and negative zeta potentials (approximately -25 mV) had desirable CUR loading amounts (5.1-6.1 %) and high CUR encapsulation efficiency (73.2-89.6 %). In vitro cellular uptake assays revealed that the cell internalization efficiencies of NPs were increased with the increase of their particle sizes, and NPs (900) showed the highest phagocytosis efficiency in macrophages among all the tested NPs. Importantly, NPs (900) exhibited significantly stronger capability to downregulate the production of the main pro-inflammatory cytokines from macrophages when they were compared with NPs (200) and NPs (500). Further animal studies suggested that oral administration of hydrogel (chitosan and alginate)-embedding NPs (900) could efficiently accumulate in colitis tissue in a manner that was comparable to that of NPs (200) and NPs (500) and could achieve the best treatment efficacy against ulcerative colitis (UC). Collectively, these findings can serve as a guideline for the rational design of nanotherapeutics with desirable accumulation profiles in colitis tissue, maximized cellular uptake efficiency in macrophages, and good therapeutic outcomes against UC., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Spinal cord injury (SCI) is one of the most debilitating injuries, and transplantation of stem cells in a scaffold is a promising strategy for treatment. However, stem cell treatment of SCI has been severely impaired by the increased generation of reactive oxygen species in the lesion microenvironment, which can lead to a high level of stem cell death and dysfunction. Herein, a MnO 2 nanoparticle (NP)-dotted hydrogel is prepared through dispersion of MnO 2 NPs in a PPFLMLLKGSTR peptide modified hyaluronic acid hydrogel. The peptide-modified hydrogel enables the adhesive growth of mesenchymal stem cells (MSCs) and nerve tissue bridging. The MnO 2 NPs alleviate the oxidative environment, thereby effectively improving the viability of MSCs. Transplantation of MSCs in the multifunctional gel generates a significant motor function restoration on a long-span rat spinal cord transection model and induces an in vivo integration as well as neural differentiation of the implanted MSCs, leading to a highly efficient regeneration of central nervous spinal cord tissue. Therefore, the MnO 2 NP-dotted hydrogel represents a promising strategy for stem-cell-based therapies of central nervous system diseases through the comprehensive regulation of pathological microenvironment complications.

Orally targeted delivery of anti-inflammatory drugs to macrophages has attracted great attention for minimizing the symptoms of ulcerative colitis (UC). In this investigation, we encapsulated curcumin (CUR) into polymeric nanoparticles (NPs), and conjugated chondroitin sulfate (CS) to their surfaces. The resulting CS-NPs had an average diameter of 281 nm, monodisperse size distribution and negatively charged surface. Cell experiments indicated that these NPs showed excellent biocompatibility, and yielded significantly higher cell internalization efficiency in Raw 264.7 macrophages than their counterparts (carboxymethyl cellulose-functionalized CUR-encapsulated NPs, CUL-NPs). Moreover, CS-NPs exhibited a dramatically stronger capacity to inhibit the secretion of the major pro-inflammatory cytokines from lipopolysaccharide-stimulated macrophages compared with CUL-NPs. In vivo experiments revealed that oral administration of chitosan/alginate hydrogel embedding CS-NPs achieved better therapeutic outcomes against UC comparied with CUL-NPs. Collectively, our results demonstrated that CS-NP-embedded hydrogel held a great promise to be developed as a macrophage-targeted drug delivery system for UC treatment., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The incidence of colonic diseases (e.g., inflammatory bowel diseases and colon cancer) is rapidly rising. Nanotherapeutic has been considered as a promising strategy in the treatment of colonic diseases. Silk fibroin (SF) has been widely used as a drug-carrier matrix. Interestingly, SF-based nanoparticles (SFNPs) have intrinsic anti-inflammatory activity, wound healing capacity and lysosomal environment-responsive drug-release property. With further investigations, the sequences of SF molecules could be precisely modified through chemical reactions or transgenic techniques to greatly improve the properties of SFNPs. Here, we review recent advances in the application of SFNPs toward the treatment of colonic diseases. We also discuss future developments that might improve the anti-inflammatory and anti-colon cancer activities of SF-based nanotherapeutics.

The requirement for the favorable therapeutics against ulcerative colitis (UC) is that anti-inflammatory drugs can be specifically internalized by macrophages and subsequently be on-demand released to suppress inflammation. Herein, we developed a type of multi-bioresponsive anti-inflammatory drug (curcumin, CUR)-loaded nanoparticles (NPs) that were derived from natural silk fibroin and followed by surface functionalization with chondroitin sulfate (CS). The generated CS-CUR-NPs had a desired average particle size (175.4 nm), a uniform size distribution and negative surface charge (-35.5 mV). Strikingly, these NPs exhibited excellent bioresponsibility when triggered with the intrinsic stimuli (acidity, glutathione and reactive oxygen species) within activated macrophages, indicating that they could conceivably confer the on-demand intracellular drug release. Furthermore, we found that CS functionalization yielded notably targeted drug delivery to macrophages, and thereby enhanced the anti-inflammatory activities of NPs. Most importantly, animal experiments revealed that these nanotherapeutics could remarkably alleviate the symptoms of UC, maintain the homeostasis of intestinal microbiota and improve the survival rate of mice with UC through the route of oral administration or intravenous injection. Our results suggest that these facilely fabricated CS-CUR-NPs, which exhibit excellent biocompatibility, multi-bioresponsive drug release and macrophage-targeted capacity, could be exploited as a promising therapeutic platform for clinical UC treatment., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Porous microparticles (MPs) have been regarded as a promising vehicle for drug delivery. Herein, porous MPs and their counterparts (nonporous MPs) were produced by a conventional emulsion-solvent evaporation method in the presence and absence of ammonium bicarbonate, and curcumin was encapsulated into these MPs during the preparation process. The obtained MPs possessed desirable diameters of around 1.2 μm and negative zeta potentials of approximately -28 mV. It was found that the release rate of curcumin was remarkably increased with the introduction of pores in MPs. Furthermore, orally administered porous MPs achieved statistically significantly better therapeutic outcomes against ulcerative colitis mouse model induced by dextran sulfate sodium, in comparison to nonporous MPs. These findings confirmed that porous MPs could be served as a promising platform for the treatment of ulcerative colitis via oral route., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Targeted delivery of chemotherapeutic drugs to tumors is a major challenge in colon cancer chemotherapy. To overcome this bottleneck, we loaded camptothecin (CPT) into polymeric nanoparticles (NPs), and further functionalized their surface with chondroitin sulfate (CS). The resulting CS-CPT-NPs had a desirable hydrodynamic diameter (289 nm), narrow particle size distribution (polydispersity index = 0.192) and neutral surface charge. Furthermore, in vitro experiments revealed that the surface functionalization of CS endowed NPs with the capacity of colon cancer-targeted drug delivery, and significantly improved the anti-colon cancer activities and pro-apoptosis effects against colon cancer cells. Strikingly, treatment of colon tumor-bearing mice with different NPs clearly indicated that CS-CPT-NPs showed much better therapeutic outcomes than non-targeted NPs and no systemic toxicity. Taken together, these results demonstrated the promising potential of CS-CPT-NP as an effective drug delivery system for colon cancer-targeted chemotherapy., (Copyright © 2019. Published by Elsevier B.V.)

To improve the penetration and accumulation of anti-inflammatory drugs in colitis tissue, we functionalized the surface of porous poly(lactic-co-glycolic acid) nanoparticles (NPs) using pluronic F127 (PF127) and loaded curcumin (CUR) into the resulting NPs to obtain porous PF127-functionalized CUR-loaded NPs (porous PF127-NPs). These NPs had an average hydrodynamic diameter of about 270 nm with a highly monodisperse size distribution, slightly negative surface charge and controllable CUR release profile. It was found that they had good biocompatibility and yielded a much higher cellular uptake rate of CUR than porous CUR-loaded NPs without PF127 modification (porous NPs). In addition, porous PF127-NPs showed a greater capacity to inhibit the major pro-inflammatory cytokines (IL-6, IL-12 and TNF-α) secreted from lipopolysaccharide-activated macrophages than porous NPs and non-porous PF127-NPs. In vivo experiments suggested that porous PF127-NPs achieved the best therapeutic outcomes against ulcerative colitis (UC) in mice compared with porous NPs and non-porous PF127-NPs. Our results clearly demonstrate that these fabricated porous PF127-NPs show a great promise as an efficient CUR nanocarrier for UC therapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Reactive oxygen species (ROS) are highly overproduced in cancerous tissues, and thus oxidation-responsive nanoparticles (NPs) have emerged as a promising drug carrier for cancer-targeted drug delivery. In this study, we successfully synthesized poly(vanillyl alcohol- co-oxalate) (PVAX) polymer with an excellent ROS-responsive capacity. A well-established emulsion-solvent evaporation method was used to fabricate PVAX-based curcumin (CUR)-loaded NPs (PVAX-NPs) and their counterparts (poly(lactic- co-glycolic acid)-based CUR-loaded NPs, PLGA-NPs). It was found that these NPs had a hydrodynamic particle size of approximately 245 nm, narrow size distribution (polydispersity index less than 0.1), negative zeta potential (around -18 mV), smooth surface appearance, and high drug encapsulation efficiency. Moreover, we found that the CUR release rate of PVAX-NPs was greatly increased in the presence of a hydrogen peroxide-rich environment due to the cleavage of polyoxalate ester bonds in PVAX polymer, resulting in the evenly distribution of CUR within the whole cancer cells. More importantly, PVAX-NPs exhibited much stronger anticancer activities and pro-apoptotic capacities than PLGA-NPs both in vitro and in vivo. These results clearly demonstrate that these ROS-responsive PVAX-NPs can be exploited as a robust anticancer drug delivery platform in chemotherapy.

Background: Oral administrations of microparticles (MPs) and nanoparticles (NPs) have been widely employed as therapeutic approaches for the treatment of ulcerative colitis (UC). However, no previous study has comparatively investigated the therapeutic efficacies of MPs and NPs., Methods: In this study, curcumin (CUR)-loaded MPs (CUR-MPs) and CUR-loaded NPs (CUR-NPs) were prepared using a single water-in-oil emulsion solvent evaporation technique. Their therapeutic outcomes against UC were further comparatively studied., Results: The resultant spherical MPs and NPs exhibited slightly negative zeta-potential with average particle diameters of approximately 1.7 µm and 270 nm, respectively. It was found that NPs exhibited a much higher CUR release rate than MPs within the same period of investigation. In vivo experiments demonstrated that oral administration of CUR-MPs and CUR-NPs reduced the symptoms of inflammation in a UC mouse model induced by dextran sulfate sodium. Importantly, CUR-NPs showed much better therapeutic outcomes in alleviating UC compared with CUR-MPs., Conclusion: NPs can improve the anti-inflammatory activity of CUR by enhancing the drug release and cellular uptake efficiency, in comparison with MPs. Thus, they could be exploited as a promising oral drug delivery system for effective UC treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Integration of biological macromolecules with inorganic materials via biomineralization has demonstrated great potential for development of nanotheranostic agents. To produce multifunctionality, integration of multiple components in the biomineralized theranostic agents is required; however, how to efficiently and reproducibly implement this is challenging. In this report, a universal biomineralization strategy is developed by incorporation of oxidization polymerization into albumin-templated biomineralization for facile synthesis of nanotheranostic agents. A series of biomineralized polymers and manganese dioxide hybrid nanoparticles (PMHNs) can be synthesized via the polymerization of various monomers, including dopamine (DA), epigallocatechin (EGC), pyrrole (PY), and diaminopyridine (DP), along with the reduction of KMnO 4 and formation of manganese dioxide nanoparticles in albumin templates. These biomineralized PMHNs demonstrate ultrahigh MRI (longitudinal relaxivity up to 38 mM -1 s -1 ) and ultrasonic (US) imaging contrasting capabilities and have excellent photothermal therapy efficacy with complete ablation of orthotopic tumors. Moreover, these biomineralized hybrid nanoparticles can be effectively excreted through the kidneys, avoiding potential systemic toxicity. Thus, integration of polymerization into biomineralization presents a strategy for the fabrication of hybrid nanomaterials, allowing the production of multifunctional and biocompatible nanotheranostic agents via a facile one-pot method.

Colon cancer is among the most widely occurring cancer types, leading to considerably high mortality rate. The current chemotherapy achieves only limited success, and more effective therapeutic strategies are urgently needed. Human colonic biopsy specimens indicate increased expression of CD98 in patients with colon cancer, suggesting that CD98 might be a potential therapeutic target and/or a receptor for targeted drug delivery in colon cancer treatment. Herein, we coloaded CD98 siRNA (siCD98) and camptothecin (CPT) into CD98 Fab'-functionalized nanoparticles (NPs). The resultant Fab'-siCD98/CPT-NPs showed good monodispersity with an average diameter of approximately 270 nm and a ζ-potential of around -24 mV. These NPs mediated efficient drug delivery to the target cancer cells and tumor tissues, producing much better anticancer and antimigration effects compared to other relevant NPs. Mouse models with orthotopic colon tumors were treated with NP-embedded hydrogel, which revealed that Fab'-siCD98/CPT-NPs exhibited a therapeutic efficacy significantly better than that of single drug-loaded NPs or nonfunctionalized siCD98/CPT-NPs. This study indicates that the Fab'-siCD98/CPT-NP/hydrogel system is able to realize specific release of NPs in the colonic lumen and enable drugs (siCD98 and CPT) to be internalized into target cells, demonstrating a notable potential for clinical applications in colon-cancer-targeted combination therapy.

TTF1‑NP is a flavonoid nanoparticle based on 5,2',4'‑trihydroxy‑6,7,5'‑trimethoxyflavone (TTF1), which is derived from the medicinal plant Sorbaria sorbifolia that grows in the Changbai Mountain. We previously demonstrated antitumor effects of TTF1‑NP in human hepatoma including induction of apoptosis and inhibition of angiogenesis, migration and invasion. Herein, we examined the effects of TTF1‑NP on autophagy and its relationship with apoptosis, and explored potential underlying mechanisms in human hepatoma cell lines. We conducted cell viability assays, Annexin V/propidium iodide double staining, Hoechst staining, monodansylcadaverine staining, transmission electron microscopy, green fluorescent protein‑light chain 3 plasmid transfection and western blots. We found that TTF1‑NP induced apoptosis and autophagy in HepG2 and SMMC‑7721 cells. Pretreatment with the autophagy inhibitor 3‑methyladenine promoted TTF1‑NP‑induced apoptosis. TTF1‑NP decreased levels of phosphorylated (p)‑Akt, p‑mTOR and p‑ERK1/2 and increased p‑JNK levels in the two cell lines. Treating cells with insulin, SP600125 and U0126 indicated that the Akt/mTOR pathway and JNK were involved in TTF1‑NP‑induced autophagy. Together, these findings suggest that TTF1‑NP induced protective apoptosis‑related autophagy by modulating the Akt/mTOR and JNK pathways in HepG2 and SMMC‑7721 cells. Therefore, autophagy may be a potential target for TTF1‑NP in human hepatoma therapy.

The successful treatment of chronic nonhealing wounds requires strategies that promote angiogenesis, collagen deposition, and re-epithelialization of the wound. Copper ions have been reported to stimulate angiogenesis; however, several applications of copper salts or oxides to the wound bed are required, leading to variable outcomes and raising toxicity concerns. We hypothesized that copper-based metal-organic framework nanoparticles (Cu-MOF NPs), referred to as HKUST-1, which are rapidly degraded in protein solutions, can be modified to slowly release Cu 2+ , resulting in reduced toxicity and improved wound healing rates. Folic acid was added during HKUST-1 synthesis to generate folic-acid-modified HKUST-1 (F-HKUST-1). The effect of folic acid incorporation on NP stability, size, hydrophobicity, surface area, and copper ion release profile was measured. In addition, cytotoxicity and in vitro cell migration processes due to F-HKUST-1 and HKUST-1 were evaluated. Wound closure rates were assessed using the splinted excisional dermal wound model in diabetic mice. The incorporation of folic acid into HKUST-1 enabled the slow release of copper ions, which reduced cytotoxicity and enhanced cell migration in vitro. In vivo, F-HKUST-1 induced angiogenesis, promoted collagen deposition and re-epithelialization, and increased wound closure rates. These results demonstrate that folic acid incorporation into HKUST-1 NPs is a simple, safe, and promising approach to control Cu 2+ release, thus enabling the direct application of Cu-MOF NPs to wounds.

Aim: To enhance the tumor accumulation and targeted drug delivery for colon cancer therapy, iRGD peptide was introduced to the surface of PEGylated camptothecin-loaded nanoparticles (NPs)., Methods: Cellular uptake, targeting specificity, biodistribution and antitumor capacity were evaluated., Results: The functionalization of iRGD facilitated tumor accumulation and cellular uptake of NPs by Colon-26 cells. Furthermore, the resultant iRGD-PEG-NPs remarkably improved the therapeutic efficacy of camptothecin in vitro and in vivo by inducing a higher degree of tumor cell apoptosis compared with PEG-NPs., Conclusion: iRGD-PEG-NP is a desired drug delivery system to facilitate the drug accumulation in orthotopic colon tumor tissues and further drug internalization by colon cancer cells.

Overcoming adverse effects and selectively delivering drug to target cells are two major challenges in the treatment of ulcerative colitis (UC). Lysine-proline-valine (KPV), a naturally occurring tripeptide, has been shown to attenuate the inflammatory responses of colonic cells. Here, we loaded KPV into hyaluronic acid (HA)-functionalized polymeric nanoparticles (NPs). The resultant HA-KPV-NPs had a desirable particle size (∼272.3 nm) and a slightly negative zeta potential (∼-5.3 mV). These NPs successfully mediated the targeted delivery of KPV to key UC therapy-related cells (colonic epithelial cells and macrophages). In addition, these KPV-loaded NPs appear to be nontoxic and biocompatible with intestinal cells. Intriguingly, we found that HA-KPV-NPs exert combined effects against UC by both accelerating mucosal healing and alleviating inflammation. Oral administration of HA-KPV-NPs encapsulated in a hydrogel (chitosan/alginate) exhibited a much stronger capacity to prevent mucosa damage and downregulate TNF-α, thus they showed a much better therapeutic efficacy against UC in a mouse model, compared with a KPV-NP/hydrogel system. These results collectively demonstrate that our HA-KPV-NP/hydrogel system has the capacity to release HA-KPV-NPs in the colonic lumen and that these NPs subsequently penetrate into colitis tissues and enable KPV to be internalized into target cells, thereby alleviating UC., (Copyright © 2016 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Tumor necrosis factor-α (TNF-α) is a major pro-inflammatory cytokine that is mainly secreted by macrophages during inflammation. Here, we synthesized a series of N-(2-hydroxy)propyl-3-trimethyl ammonium chitosan chlorides (HTCCs), and then used a complex coacervation technique or tripolyphosphate (TPP)-assisted ionotropic gelation strategy to complex the HTCCs with TNF-α siRNA (siTNF) to form nanoparticles (NPs). The resultant NPs had a desirable particle size (210-279nm), a slightly positive zeta potential (14-22mV), and negligible cytotoxicity against Raw 264.7 macrophages and colon-26 cells. Subsequent cellular uptake tests demonstrated that the introduction of TPP to the NPs markedly increased their cellular uptake efficiency (to nearly 100%) compared with TPP-free NPs, and yielded a correspondingly higher intracellular concentration of siRNA. Critically, in vitro gene silencing experiments revealed that all of the TPP-containing NPs showed excellent efficiency in inhibiting the mRNA expression level of TNF-α (by approximately 85-92%, which was much higher than that obtained using Oligofectamine/siTNF complexes). Collectively, these results obviously suggest that our non-toxic TPP-containing chitosan-based NPs can be exploited as efficient siTNF carriers for the treatment of inflammatory diseases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

TTF1-NP (5,2',4'-trihydroxy-6,7,5'-trimethoxyflavone nanoparticles), derived from the traditional Changbai Mountain medicinal plant Sorbaria sorbifolia (SS), has been showed its anti-cancer effect in various liver cancer cell types and tissues. The present study was designed to evaluate the antitumor mechanism of the TTF1-NP against HepG2 hepatoma cells and HepG2 cells-induced hepatocarcinoma (HCC) in nude mouse model. Here we demonstrated that TTF1-NP inhibits tube formation of HUVECs and HepG2 cell migration and invasion, and inhibits tumor growth in nude mice implanted with HepG2 cells through the downregulation of STAT3 protein and activation, along with VEGF, KDR, bFGF, MMP2 and MMP9 levels. We further revealed that TTF1-NP decreased the DNA-binding capacity of STAT3. Together our results provide a mechanism by which TTF1-NP suppresses cancer cell migration, invasion and angiogenesis through the action of STAT3 and suggests TTF1-NP as a potential therapy for hepatocellular cancer treatment.

Context: Glioma is a common malignant brain tumor originating in the central nervous system. Efficient delivery of therapeutic agents to the cells and tissues is a difficult challenge. Co-delivery of anticancer drugs into the cancer cells or tissues by multifunctional nanocarriers may provide a new paradigm in cancer treatment., Objective: In this study, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) were constructed for co-delivery of vincristine (VCR) and temozolomide (TMZ) to develop the synergetic therapeutic action of the two drugs. The antitumor effects of these two systems were compared to provide a better choice for gliomatosis cerebri treatment., Methods: VCR- and TMZ-loaded SLNs (VT-SLNs) and NLCs (VT-NLCs) were formulated. Their particle size, zeta potential, drug encapsulation efficiency (EE) and drug loading capacity were evaluated. The single TMZ-loaded SLNs and NLCs were also prepared as contrast. Anti-tumor efficacies of the two kinds of carriers were evaluated on U87 malignant glioma cells and mice bearing malignant glioma model., Results: Significantly better glioma inhibition was observed on NLCs formulations than SLNs, and dual drugs displayed the highest antitumor efficacy in vivo and in vitro than all the other formulations used., Conclusion: VT-NLCs can deliver VCR and TMZ into U87MG cells more efficiently, and inhibition efficacy is higher than VT-SLNs. This dual drugs-loaded NLCs could be an outstanding drug delivery system to achieve excellent therapeutic efficiency for the treatment of malignant gliomatosis cerebri.

The use of nanotechnology for drug delivery has shown great promise for improving cancer treatment. However, potential toxicity, hazardous environmental effects, issues with large-scale production, and potential excessive costs are challenges that confront their further clinical applications. Here, we describe a nanovector made from ginger-derived lipids that can serve as a delivery platform for the therapeutic agent doxorubicin (Dox) to treat colon cancer. We created nanoparticles from ginger and reassembled their lipids into ginger-derived nanovectors (GDNVs). A subsequent characterization showed that GDNVs were efficiently taken up by colon cancer cells. Viability and apoptosis assays and electric cell-substrate impedance-sensing technology revealed that GDNVs exhibited excellent biocompatibility up to 200 μmol/l; by contrast, cationic liposomes at the same concentrations decreased cell proliferation and increased apoptosis. GDNVs were capable of loading Dox with high efficiency and showed a better pH-dependent drug-release profile than commercially available liposomal-Dox. Modified GDNVs conjugated with the targeting ligand folic acid mediated targeted delivery of Dox to Colon-26 tumors in vivo and enhanced the chemotherapeutic inhibition of tumor growth compared with free drug. Current experiments explore the feasibility of producing nature-derived nanoparticles that are effective as a treatment vehicle while potentially attenuating the issues related to traditional synthetic nanoparticles.

Combination therapy is an emerging strategy that is under intensive preclinical investigation for the treatment of various diseases. CD98 is highly overexpressed on the surfaces of epithelial cells and macrophages in the colon tissue with ulcerative colitis (UC), which is usually associated with mucosal damage and inflammation. We previously proved that CD98 siRNA (siCD98)-induced down-regulation of CD98 in colitis tissue decreased the severity of UC to a certain extent. In an effort to further improve the therapeutic efficacy, we aim to simultaneously deliver siCD98 in combination with a potent anti-inflammatory agent, curcumin (CUR), using hyaluronic acid (HA)-functionalized polymeric nanoparticles (NPs). The resultant spherical HA-siCD98/CUR-NPs are featured by a desirable particle size (∼246 nm) and slightly negative zeta potential (∼-14 mV). The NPs functionalized with HA are able to guide the co-delivery of drugs to the targeted cells related to UC therapy (colonic epithelial cells and macrophages). Compared to either siCD98- or CUR-based monotherapy, co-delivery of siCD98 and CUR by HA-functionalized NPs can exert combinational effects against UC by protecting the mucosal layer and alleviating inflammation both in vitro and in vivo . This study shows the promising capability of the co-delivered siCD98 and CUR for boosting the conventional monotherapy via this novel nanotherapeutic agent, which offers a structurally simple platform for orally administered delivery of drugs to target cells in UC therapy., Competing Interests: The authors have declared that no competing interest exists.