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Objective: Nimodipine still represents a unique selling point in the prevention of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). Its intrathecal effect is limited by a low oral bioavailability, leading to the development of nanocarrier systems to overcome this limitation. This study investigated the ultrasound-induced release profile of nimodipine from drug-loaded copolymers in artificial cerebrospinal fluid (CSF) within 72 h after a singular versus repeated sonication. Methods: Pluronic® F127 copolymers (Sigma-Aldrich, Taufkirchen, Germany)were loaded with nimodipine by direct dissolution. Spontaneous and on-demand drug release by ultrasound (1 MHz at 1.7 W/cm2) was determined in artificial cerebrospinal fluid using the dialysis bag method. Nimodipine concentrations were measured at predefined time points within 72 h of sonication. Results: Spontaneous release of nimodipine was enhanced by ultrasound application with significantly increased nimodipine concentrations two hours after a repeated sonication compared to a singular sonication (median 1.62 vs. 17.48 µg/µL, p = 0.04). A further trend was observed after four hours (median 1.82 vs. 22.09 µg/µL, p = 0.06). There was no difference in the overall nimodipine concentrations between the groups with a singular versus repeated sonication (357.2 vs. 540.3 µg/µL, p = 0.60) after 72 h. Conclusions: Repeated sonication resulted in an acceleration of nimodipine release from the drug-loaded copolymer in a CSF medium. These findings confirm the proof of principle of an on-demand guidance of nimodipine release from nimodipine-loaded nanodrugs by means of ultrasound, which suggests that evaluating the concept in an animal model may be appropriate. [ABSTRACT FROM AUTHOR]

Crataegus aronia L. is commonly known as Hawthorn and used in traditional Jordan medicine. In this research, the phytochemical compounds were studied qualitatively and quantitatively using fruit extract of the wild C. aronia collected from Jordan. The total phenolic, total tannin, total alkaloid, and total flavonoid contents of the fruit extract of C. aronia was determined using standard methods. The antioxidant activity was evaluated using the DPPH (2, 2-diphenyl-1-picrylhydrazyl) radical scavenging assay. Biogenic synthesis of magnesium oxide nanoparticles (MgONPs) using the plant extract was carried out. The purified nanoparticles were characterized by UV-visible spectroscopy, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Scanning electron microscopy (SEM), and Transmission electron microscopy (TEM). The cytotoxic effect of the MgONPs against colon cancer (CaCo2) cell line was evaluated using the MTT (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric assay. The MgO nanoparticles had smooth surface and randomly arranged with an average particle size of 20-40 nm. The nanoparticles exhibited cytotoxic activity against colon cancer cell lines with an IC50 value of 98 µg/mL. The study concluded that MgONPs synthesized using fruits of Crataegus aronia have potential anticancer activity against CaCo2 cell lines. [ABSTRACT FROM AUTHOR]

In recent years, the development of green multifunctional nanoformulations with specific anticancer activity has gained importance among scientists. In the present study, Camelia sinensis extract/CuO nanoparticles (CSE/CuO NPs) and cisplatin (Cis)-loaded CSE/CuO NPs were prepared and characterized by various TEM, XRD, FTIR, and UV-Vis techniques. The antioxidant properties of the green CSE/CuO NPs were evaluated using the CUPRIC Reducing Antioxidant Capacity (CUPRAC) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS)/HRP methods. The drug release profile of the NPs was studied at pH 7.4 and pH 5.5. Additionally, the cytotoxic effects of CSE/CuO NPs and Cis-loaded CSE/CuO NPs on MIA-PaCa-2 pancreatic cancer were evaluated using the MTT assay and compared with normal HUVEC cells. Subsequently, the apoptotic activity of CSE/CuO NPs and Cis-loaded CSE/CuO NPs on MIA-PaCa-2 cells was evaluated using Annexin-V FITC, and their effects on multi-drug resistance were determined using the ABCG2 antibody by flow cytometric analysis. Our results showed that Cis-loaded CSE/CuO NPs exhibited a pH-sensitive drug release profile. CSE/CuO NPs were highly cytotoxic to MIA-PaCa-2 pancreatic cancer cells, while exhibiting very low cytotoxicity to HUVEC cells. Moreover, CSE/CuO NPs and Cis-loaded CSE/CuO NPs were found to have higher apoptotic activity and lower drug resistance compared to free Cis. Although many studies have been conducted with CSE, this study was the first to show that CSE/CuO NPs were dominantly and selectively effective against pancreatic cancer, and resistance to Cis and its side effects could be significantly reduced by CSE-derived nanocarriers. Additionally, for the first time, the antioxidant property was investigated by applying CUPRAC and ABTS methods. [ABSTRACT FROM AUTHOR]

[Display omitted] Hepatocellular carcinoma (HCC) exhibits a low response to immunotherapy due to the dense extracellular matrix (ECM) filled with immunosuppressive cells including dendritic cells (DCs) of blocked maturation. Herein, we develop a nanoprodrug self-assembled from polyethylene glycol-poly-4-borono- l -phenylalanine (mPEG-PBPA) conjugating with quercetin (QUE) via boronic ester bonds. In addition, an immune adjuvant of imiquimod (R837) is incorporated. The nanodrug (denoted as Q&R@NPs) is prepared from a simple mixing means with a high loading content of QUE reaching more than 30%. Owing to the acid and reactive oxygen species (ROS) sensitivities of boronic ester bonds, Q&R@NPs can respond to the tumor microenvironment (TME) and release QUE and R837 to synchronously exert multicellular regulation functions. Specifically, QUE inhibits the activation state of hepatic stellate cells and reduces highly expressed programmed death receptor ligand 1 (PD-L1) on tumor cells, meanwhile R837 exposes calreticulin on tumor cell surface as an "eat me" signal and leads to a large number of DCs maturing for enhanced antigen presentation. Consequently, the cooperative immune regulation results in a remodeled TME with high infiltration of cytotoxic T lymphocytes for enhanced HCC immunotherapy, which demonstrates an effective immunotherapy paradigm for dense ECM characterized solid tumors with high PD-L1 expression. [ABSTRACT FROM AUTHOR]

Insufficient therapeutic strategies for acute kidney injury (AKI) necessitate precision therapy targeting its pathogenesis. This study reveals the new mechanism of the marine-derived anti-AKI agent, piericidin glycoside S14, targeting peroxiredoxin 1 (PRDX1). By binding to Cys83 of PRDX1 and augmenting its peroxidase activity, S14 alleviates kidney injury efficiently in Prdx1-overexpression (Prdx1-OE) mice. Besides, S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production. Due to the limited druggability of S14 with low bioavailability (2.6%) and poor renal distribution, a pH-sensitive kidney-targeting dodecanamine-chitosan nanoparticle system is constructed to load S14 for precise treatment of AKI. l-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1 (Kim-1)-overexpressed cells. The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly. By encapsulation with micelles, the AUC0‒t, half-life time, and renal distribution of S14 increase 2.5-, 1.8-, and 3.1-fold, respectively. The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDP-glycosyltransferase (UGT)-mediated biotransformation. In summary, this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology, thereby driving advancements in marine drug development for AKI.

Exosomes are found in various tissues of the body and carry abundant contents including nucleic acids, proteins, and metabolites, which continuously flow between cells of various tissues and mediate important intercellular communication. In addition, exosomes from different cellular sources possess different physiopathological immunomodulatory effects, which are closely related to the immune regeneration of normal or abnormal organs and tissues. Here, we focus on the mechanistic interactions between exosomes and the human immune system, introduce the immuno-regenerative therapeutic potential of exosomes in common clinical immune-related diseases, such as infectious diseases, autoimmune diseases, and tumors, and reveal the safety and efficacy of exosomes as a novel cell-free immune regenerative therapy. [ABSTRACT FROM AUTHOR]

Insufficient therapeutic strategies for acute kidney injury (AKI) necessitate precision therapy targeting its pathogenesis. This study reveals the new mechanism of the marine-derived anti-AKI agent, piericidin glycoside S14, targeting peroxiredoxin 1 (PRDX1). By binding to Cys83 of PRDX1 and augmenting its peroxidase activity, S14 alleviates kidney injury efficiently in Prdx1 -overexpression (Prdx1 -OE) mice. Besides, S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production. Due to the limited druggability of S14 with low bioavailability (2.6%) and poor renal distribution, a pH-sensitive kidney-targeting dodecanamine-chitosan nanoparticle system is constructed to load S14 for precise treatment of AKI. l -Serine conjugation to chitosan imparts specificity to kidney injury molecule-1 (Kim-1)-overexpressed cells. The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly. By encapsulation with micelles, the AUC 0‒ t , half-life time, and renal distribution of S14 increase 2.5-, 1.8-, and 3.1-fold, respectively. The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDP-glycosyltransferase (UGT)-mediated biotransformation. In summary, this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology, thereby driving advancements in marine drug development for AKI. Marine-derived S14 targets PRDX1 and regulates PRDX1/Nrf2 to mitigate AKI-induced reactive oxygen species. A S14-loaded Kim-1-targeted nanodelivery system was established to enhance renal biodistribution and pharmacokinetics properties for AKI therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Osteosarcoma is a malignant tumor originating from bone tissue that progresses rapidly and has a poor patient prognosis. Immunotherapy has shown great potential in the treatment of osteosarcoma. However, the immunosuppressive microenvironment severely limits the efficacy of osteosarcoma treatment. The dual pH-sensitive nanocarrier has emerged as an effective antitumor drug delivery system that can selectively release drugs into the acidic tumor microenvironment. Here, we prepared a dual pH-sensitive nanocarrier, loaded with the photosensitizer Chlorin e6 (Ce6) and CD47 monoclonal antibodies (aCD47), to deliver synergistic photodynamic and immunotherapy of osteosarcoma. On laser irradiation, Ce6 can generate reactive oxygen species (ROS) to kill cancer cells directly and induces immunogenic tumor cell death (ICD), which further facilitates the dendritic cell maturation induced by blockade of CD47 by aCD47. Moreover, both calreticulin released during ICD and CD47 blockade can accelerate phagocytosis of tumor cells by macrophages, promote antigen presentation, and eventually induce T lymphocyte-mediated antitumor immunity. Overall, the dual pH-sensitive nanodrug loaded with Ce6 and aCD47 showed excellent immune-activating and anti-tumor effects in osteosarcoma, which may lay the theoretical foundation for a novel combination model of osteosarcoma treatment. [ABSTRACT FROM AUTHOR]

Purpose of the study: the creation of a dextran coating on cerium oxide crystals using different ratios of cerium and dextran to synthesize nanocomposites, and the selection of the best nanocomposite to develop a nanodrug that accelerates quality wound healing with a new type of antimicrobial effect. Materials and methods: Nanocomposites were synthesized using cerium nitrate and dextran polysaccharide (6000 Da) at four different initial ratios of Ce(NO3)3x6H2O to dextran (by weight)—1:0.5 (Ce0.5D); 1:1 (Ce1D); 1:2 (Ce2D); and 1:3 (Ce3D). A series of physicochemical experiments were performed to characterize the created nanocomposites: UV-spectroscopy; X-ray phase analysis; transmission electron microscopy; dynamic light scattering and IR-spectroscopy. The biomedical effects of nanocomposites were studied on human fibroblast cell culture with an evaluation of their effect on the metabolic and proliferative activity of cells using an MTT test and direct cell counting. Antimicrobial activity was studied by mass spectrometry using gas chromatography–mass spectrometry against E. coli after 24 h and 48 h of co-incubation. Results: According to the physicochemical studies, nanocrystals less than 5 nm in size with diffraction peaks characteristic of cerium dioxide were identified in all synthesized nanocomposites. With increasing polysaccharide concentration, the particle size of cerium dioxide decreased, and the smallest nanoparticles (<2 nm) were in Ce2D and Ce3D composites. The results of cell experiments showed a high level of safety of dextran nanoceria, while the absence of cytotoxicity (100% cell survival rate) was established for Ce2D and C3D sols. At a nanoceria concentration of 10−2 M, the proliferative activity of fibroblasts was statistically significantly enhanced only when co-cultured with Ce2D, but decreased with Ce3D. The metabolic activity of fibroblasts after 72 h of co-cultivation with nano composites increased with increasing dextran concentration, and the highest level was registered in Ce3D; from the dextran group, differences were registered in Ce2D and Ce3D sols. As a result of the microbiological study, the best antimicrobial activity (bacteriostatic effect) was found for Ce0.5D and Ce2D, which significantly inhibited the multiplication of E. coli after 24 h by an average of 22–27%, and after 48 h, all nanocomposites suppressed the multiplication of E. coli by 58–77%, which was the most pronounced for Ce0.5D, Ce1D, and Ce2D. Conclusions: The necessary physical characteristics of nanoceria–dextran nanocomposites that provide the best wound healing biological effects were determined. Ce2D at a concentration of 10−3 M, which stimulates cell proliferation and metabolism up to 2.5 times and allows a reduction in the rate of microorganism multiplication by three to four times, was selected for subsequent nanodrug creation. [ABSTRACT FROM AUTHOR]

As global population and lifestyles change, osteoarthritis (OA) is becoming a major healthcare challenge world. OA, a chronic condition characterized by inflammatory and degeneration, often present with joint pain and can lead to irreversible disability. While there is currently no cure for OA, it is commonly managed using nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and glucosamine. Although these treatments can alleviate symptoms, it is difficult to effectively deliver and sustain therapeutic agents within joints. The emergence of nanotechnology, particularly in form of smart nanomedicine, has introduced innovative therapeutic approaches for OA treatment. Nanotherapeutic strategies offer promising advantages, including more precise targeting of affected areas, prolonged therapeutic effects, enhanced bioavailability, and reduced systemic toxicity compared to traditional treatments. While nanoparticles show potential as a viable delivery system for OA therapies based on encouraging lab-based and clinical trials results, there remails a considerable gap between current research and clinical application. This review highlights recent advances in nanotherapy for OA and explore future pathways to refine and optimize OA treatments strategies.

Abstract Endocrine therapy is standard for hormone receptor–positive (HR+) breast cancer treatment. However, current strategies targeting estrogen signaling pay little attention to estradiol metabolism in the liver and is usually challenged by treatment failure. In a previous study, we demonstrated that the natural compound naringenin (NAR) inhibited HR+ breast cancer growth by activating estrogen sulfotransferase (EST) expression in the liver. Nevertheless, the poor water solubility, low bio-barrier permeability, and non-specific distribution limited its clinical application, particularly for oral administration. Here, a novel nano endocrine drug NAR-cell penetrating peptide-galactose nanoparticles (NCG) is reported. We demonstrated that NCG presented specific liver targeting and increased intestinal barrier permeability in both cell and zebrafish xenotransplantation models. Furthermore, NCG showed liver targeting and enterohepatic circulation in mouse breast cancer xenografts following oral administration. Notably, the cancer inhibition efficacy of NCG was superior to that of both NAR and the positive control tamoxifen, and was accompanied by increased hepatic EST expression and reduced estradiol levels in the liver, blood, and tumor tissue. Moreover, few side effects were observed after NCG treatment. Our findings reveal NCG as a promising candidate for endocrine therapy and highlight hepatic EST targeting as a novel therapeutic strategy for HR+ breast cancer. Graphical Abstract

Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8+ T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy. Schematic illustration of preparation and CCLM-targeted therapy of engineered cell membrane-camouflaged nanodrug. (A) Preparation of engineered cell membrane-camouflaged nanoparticles co-delivered with CDK inhibitor (CDKi) and anti-mouse/human programmed death ligand 1 antibody (aPD-L1) in response to extracellular acidity of tumor microenvironment. (B) Multifunctional nanodrug targets CDKs in colon cancer cell and tumor-associated myeloid cell (TAMC) to activate aPD-L1 immunotherapy against liver metastasis of immune-desert colon cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

The integration of a multidimensional treatment dominated by active ingredients of traditional Chinese medicine (TCM), including enhanced chemotherapy and synergistically amplification of oxidative damage, into a nanoplatform would be of great significance for furthering accurate and effective cancer treatment with the active ingredients of TCM. Herein, in this study, we designed and synthesized four matrine-proteolysis-targeting chimeras (PROTACs) (depending on different lengths of the chains named LST-1, LST-2, LST-3, and LST-4) based on PROTAC technology to overcome the limitations of matrine. LST-4, with better anti-tumor activity than matrine, still degrades p-Erk and p-Akt proteins. Moreover, LST-4 NPs formed via LST-4 self-assembly with stronger anti-tumor activity and glutathione (GSH) depletion ability could be enriched in lysosomes through their outstanding enhanced permeability and retention (EPR) effect. Then, we synthesized LST-4@ZnPc NPs with a low-pH-triggered drug release property that could release zinc(II) phthalocyanine (ZnPc) in tumor sites. LST-4@ZnPc NPs combine the application of chemotherapy and phototherapy, including both enhanced chemotherapy from LST-4 NPs and the synergistic amplification of oxidative damage, through increasing the reactive oxygen species (ROS) by photodynamic therapy (PDT), causing an GSH decrease via LST-4 mediation to effectively kill tumor cells. Therefore, multifunctional LST-4@ZnPc NPs are a promising method for killing cancer cells, which also provides a new paradigm for using natural products to kill tumors. [ABSTRACT FROM AUTHOR]

Endocrine therapy is standard for hormone receptor–positive (HR+) breast cancer treatment. However, current strategies targeting estrogen signaling pay little attention to estradiol metabolism in the liver and is usually challenged by treatment failure. In a previous study, we demonstrated that the natural compound naringenin (NAR) inhibited HR+ breast cancer growth by activating estrogen sulfotransferase (EST) expression in the liver. Nevertheless, the poor water solubility, low bio-barrier permeability, and non-specific distribution limited its clinical application, particularly for oral administration. Here, a novel nano endocrine drug NAR-cell penetrating peptide-galactose nanoparticles (NCG) is reported. We demonstrated that NCG presented specific liver targeting and increased intestinal barrier permeability in both cell and zebrafish xenotransplantation models. Furthermore, NCG showed liver targeting and enterohepatic circulation in mouse breast cancer xenografts following oral administration. Notably, the cancer inhibition efficacy of NCG was superior to that of both NAR and the positive control tamoxifen, and was accompanied by increased hepatic EST expression and reduced estradiol levels in the liver, blood, and tumor tissue. Moreover, few side effects were observed after NCG treatment. Our findings reveal NCG as a promising candidate for endocrine therapy and highlight hepatic EST targeting as a novel therapeutic strategy for HR+ breast cancer. [ABSTRACT FROM AUTHOR]

The term cosmetics refers to any substances or products intended for external application on the skin with the aim of protection and better appearance of the skin surface. The skin delivery system promotes the controlled and targeted delivery of active ingredients. The development of this system has been driven by challenges encountered with conventional cosmeceuticals, including low skin retention of active components, limited percutaneous penetration, poor water dispersion of insoluble active ingredients, and instability of effective components. The aim is to create cosmeceuticals that can effectively overcome these issues. This review focuses on various nanocarriers used in cosmeceuticals currently and their applications in skin care, hair care, oral care, and more. The importance of nanotechnology in the sphere of research and development is growing. It provides solutions to various problems faced by conventional technologies, methods, and product formulations thus taking hold of the cosmetic industry as well. Nowadays, consumers are investing in cosmetics only for better appearance thus problems like wrinkles, ageing, hair loss, and dandruff requires to be answered proficiently. Nanocarriers not only enhance the efficacy of cosmeceutical products, providing better and longer-lasting effects, but they also contribute to the improved aesthetic appearance of the products. This dual benefit not only enhances the final quality and efficacy of the product but also increases consumer satisfaction. Additionally, nanocarriers offer protection against UV rays, further adding to the overall benefits of the cosmeceutical product. Figure 1 represents various advantages of nanocarriers used in cosmeceuticals. Nanotechnology is also gaining importance due to their high penetration of actives in the deeper layers of skin. It can be said that nanotechnology is taking over all the drawbacks of the traditional products. Thus, nanocarriers discussed in this review are used in nanotechnology to deliver the active ingredient of the cosmeceutical product to the desired site. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) has emerged as a significant health concern among the elderly population, with increasing attention paid to ferroptosis-induced OA in recent years. However, the prolonged use of nonsteroidal anti-inflammatory drugs or corticosteroids can lead to a series of side effects and limited therapeutic efficacy. This study aimed to employ the Mannich condensation reaction between epigallocatechin-3-gallate (EGCG) and selenomethionine (SeMet) to efficiently synthesize polyphenol-based nanodrugs in aqueous media for treating OA. Molecular biology experiments demonstrated that EGCG-based nanodrugs (ES NDs) could effectively reduce glutathione peroxidase 4 (GPX4) inactivation, abnormal Fe2+ accumulation, and lipid peroxidation induced by oxidative stress, which ameliorated the metabolic disorder of chondrocytes and other multiple pathological processes triggered by ferroptosis. Moreover, imaging and histopathological analysis of the destabilization of the medial meniscus model in mice confirmed that ES NDs exhibiting significant therapeutic effects in relieving OA. The intra-articular delivery of ES NDs represents a promising approach for treating OA and other joint inflammatory diseases.

Objective: Nimodipine still represents a unique selling point in the prevention of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). Its intrathecal effect is limited by a low oral bioavailability, leading to the development of nanocarrier systems to overcome this limitation. This study investigated the ultrasound-induced release profile of nimodipine from drug-loaded copolymers in artificial cerebrospinal fluid (CSF) within 72 h after a singular versus repeated sonication. Methods: Pluronic® F127 copolymers (Sigma-Aldrich, Taufkirchen, Germany)were loaded with nimodipine by direct dissolution. Spontaneous and on-demand drug release by ultrasound (1 MHz at 1.7 W/cm2) was determined in artificial cerebrospinal fluid using the dialysis bag method. Nimodipine concentrations were measured at predefined time points within 72 h of sonication. Results: Spontaneous release of nimodipine was enhanced by ultrasound application with significantly increased nimodipine concentrations two hours after a repeated sonication compared to a singular sonication (median 1.62 vs. 17.48 µg/µL, p = 0.04). A further trend was observed after four hours (median 1.82 vs. 22.09 µg/µL, p = 0.06). There was no difference in the overall nimodipine concentrations between the groups with a singular versus repeated sonication (357.2 vs. 540.3 µg/µL, p = 0.60) after 72 h. Conclusions: Repeated sonication resulted in an acceleration of nimodipine release from the drug-loaded copolymer in a CSF medium. These findings confirm the proof of principle of an on-demand guidance of nimodipine release from nimodipine-loaded nanodrugs by means of ultrasound, which suggests that evaluating the concept in an animal model may be appropriate.

Colorectal cancer (CRC) is one of the most prevalent and deadly malignancies that can be influenced by Fusobacterium nucleatum (Fn), a bacterium that promotes tumor development and chemoresistance, resulting in limited therapeutic efficacy. Traditional antibiotics cannot effectively eliminate Fn at tumor site due to issues like biofilm formation, while chemotherapy alone fails to suppress tumor progression. Therefore, the development of new methods to eliminate Fn and promote antitumor efficacy is of great significance for improving the outcome of CRC treatment. Herein, we developed a nanodrug (OPPL) that integrates oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) and an amphiphilic polymer (PPL) to deliver the platinum prodrug and antimicrobial lauric acid (LA) for enhancing the treatment of CRC. We demonstrated that OPPL can synergistically enhance antibacterial and biofilm disruption activities against Fn along with the antimicrobial LA by producing reactive oxygen species (ROS) through its peroxidase-like activity. Furthermore, the OPPL nanodrug can increase intracellular ROS, promote lipid peroxides and deplete glutathione, leading to ferroptosis. By combining chemotherapy and induced ferroptosis, the OPPL nanodrug exhibited high cytotoxicity against CRC cells. In vivo studies showed that the OPPL nanodrug could enhance tumor accumulation, enable magnetic resonance imaging, suppresse tumor growth, and inhibit growth of intratumor Fn. These results suggest that OPPL is an effective and promising candidate for the treatment of Fn -infected CRC. The enrichment of Fusobacterium nucleatum (Fn) in colorectal cancer is reported to exacerbate tumor malignancy and is particularly responsible for chemoresistance. To this respect, we strategically elaborated multifaceted therapeutics, namely OPPL nanodrug, combining oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) with a polymer containing a platinum prodrug and antimicrobial lauric acid. The O-SPION components exert distinctive peroxidase-like activity, capable of stimulating Fenton reactions selectively in the tumor microenvironment, consequently accounting for the progressive production of reactive oxygen species. Hence, O-SPIONs have been demonstrated to not only supplement the antimicrobial activities of lauric acid in overcoming Fn -induced chemoresistance but also stimulate potent tumor ferroptosis. Our proposed dual antimicrobial and chemotherapeutic nanodrug provides an appreciable strategy for managing challenging Fn -infected colorectal cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Traditional Chinese Medicines (TCMs) have been used for centuries for the treatment and management of various diseases. However, their effective delivery to targeted sites may be a major challenge due to their poor water solubility, low bioavailability, and potential toxicity. Nanocarriers, such as liposomes, polymeric nanoparticles, inorganic nanoparticles and organic/inorganic nanohybrids based on active constituents from TCMs have been extensively studied as a promising strategy to improve the delivery of active constituents from TCMs to achieve a higher therapeutic effect with fewer side effects compared to conventional formulations. This review summarizes the recent advances in nanocarrier-based delivery systems for various types of active constituents of TCMs, including terpenoids, polyphenols, alkaloids, flavonoids, and quinones, from different natural sources. This review covers the design and preparation of nanocarriers, their characterization, and in vitro/vivo evaluations. Additionally, this review highlights the challenges and opportunities in the field and suggests future directions for research. Nanocarrier-based delivery systems have shown great potential in improving the therapeutic efficacy of TCMs, and this review may serve as a comprehensive resource to researchers in this field. Graphical abstract

Abstract Background Hypoxia, a common characteristic of the tumour microenvironment, is involved in tumour progression and immune evasion. Targeting the hypoxic microenvironment has been implicated as a promising antitumour therapeutic strategy. TH-302 can be selectively activated under hypoxic conditions. However, the effectiveness of TH-302 in gastric cancer combined immunotherapy remains unclear. Methods We designed mPEG-PLGA-encapsulated TH-302 (TH-302 NPs) to target the hypoxic area of tumour tissues. A particle size analyzer was used to measure the average size and zeta potential of TH-302 NPs. The morphology was observed by transmission electron microscopy and scanning electron microscopy. The hypoxic area of tumour tissues was examined by immunofluorescence assays using pimonidazole. Flow cytometry analysis was performed to measure the levels of TNF-α, IFN-γ, and granzyme B. The synergistic antitumour activity of the combination of TH-302 NPs with anti-PD-1 (α-PD-1) therapy was assessed in vitro and in vivo. Haematoxylin and eosin staining of major organs and biochemical indicator detection were performed to investigate the biological safety of TH-302 NPs in vivo. Results TH-302 NPs inhibited the proliferation and promoted the apoptosis of gastric cancer cells under hypoxic conditions. In vitro and in vivo experiments confirmed that TH-302 NPs could effectively alleviate tumour hypoxia. TH-302 NPs exhibited high bioavailability, effective tumour-targeting ability and satisfactory biosafety. Moreover, the combination of TH-302 NPs with α-PD-1 significantly improved immunotherapeutic efficacy in vivo. Mechanistically, TH-302 NPs reduced the expression of HIF-1α and PD-L1, facilitated the infiltration of CD8+ T cells and increased the levels of TNF-α, IFN-γ, and granzyme B in tumours, thereby enhancing the efficacy of α-PD-1 therapy. Conclusion TH-302 NPs alleviated the hypoxic tumour microenvironment and enhanced the efficacy of PD-1 blockade. Our results provide evidence that TH-302 NPs can be used as a safe and effective nanodrug for combined immunotherapy in gastric cancer treatment.

Purpose of the study: the creation of a dextran coating on cerium oxide crystals using different ratios of cerium and dextran to synthesize nanocomposites, and the selection of the best nanocomposite to develop a nanodrug that accelerates quality wound healing with a new type of antimicrobial effect. Materials and methods: Nanocomposites were synthesized using cerium nitrate and dextran polysaccharide (6000 Da) at four different initial ratios of Ce(NO3)3x6H2O to dextran (by weight)—1:0.5 (Ce0.5D); 1:1 (Ce1D); 1:2 (Ce2D); and 1:3 (Ce3D). A series of physicochemical experiments were performed to characterize the created nanocomposites: UV-spectroscopy; X-ray phase analysis; transmission electron microscopy; dynamic light scattering and IR-spectroscopy. The biomedical effects of nanocomposites were studied on human fibroblast cell culture with an evaluation of their effect on the metabolic and proliferative activity of cells using an MTT test and direct cell counting. Antimicrobial activity was studied by mass spectrometry using gas chromatography–mass spectrometry against E. coli after 24 h and 48 h of co-incubation. Results: According to the physicochemical studies, nanocrystals less than 5 nm in size with diffraction peaks characteristic of cerium dioxide were identified in all synthesized nanocomposites. With increasing polysaccharide concentration, the particle size of cerium dioxide decreased, and the smallest nanoparticles (−2 M, the proliferative activity of fibroblasts was statistically significantly enhanced only when co-cultured with Ce2D, but decreased with Ce3D. The metabolic activity of fibroblasts after 72 h of co-cultivation with nano composites increased with increasing dextran concentration, and the highest level was registered in Ce3D; from the dextran group, differences were registered in Ce2D and Ce3D sols. As a result of the microbiological study, the best antimicrobial activity (bacteriostatic effect) was found for Ce0.5D and Ce2D, which significantly inhibited the multiplication of E. coli after 24 h by an average of 22–27%, and after 48 h, all nanocomposites suppressed the multiplication of E. coli by 58–77%, which was the most pronounced for Ce0.5D, Ce1D, and Ce2D. Conclusions: The necessary physical characteristics of nanoceria–dextran nanocomposites that provide the best wound healing biological effects were determined. Ce2D at a concentration of 10−3 M, which stimulates cell proliferation and metabolism up to 2.5 times and allows a reduction in the rate of microorganism multiplication by three to four times, was selected for subsequent nanodrug creation.

The high incidence of metastases remains a major hurdle for triple negative breast cancer (TNBC) treatment. Herein, we developed a fairly safe anticancer nanodrug for TNBC treatment by loading Epigallocatechin-3-gallate (EGCG) in cross-linked lipoic acid vesicles (EGCG@cLAVs), which cannot only directly kill TNBC cells through inducing apoptosis, but also significantly suppress the TNBC metastasis by metalloproteinases (MMPs) inhibition, a key event in tumor extracellular matrix (ECM) remodeling. The cytotoxicity assay revealed that the ICEGCG 50 of EGCG@cLAVs (85.1 μM) fell in the range of common cytotoxic drugs. The in vitro antimetastasis results disclosed that the EGCG@cLAVs effectively suppressed the migration and invasion of TNBC cells (4T1) with low wound healing rate and relative invasion rate of 19.10 ± 2.12% and 15.0 ± 1.63%, 4.0 and 6.7 times lower than that of control, respectively. The outcomes of animal models revealed that EGCG@cLAVs not only achieved the comparable antitumor effect to that of first-line chemotherapeutic drug DOX, but also reduced the number of lung metastatic nodules from 31.4 (DOX) to 1.4. This nanodrug provides a promising candidate for TNBC therapy.

Selective suppression of tumor necrosis factor (TNF) α-TNF receptor 1 (TNFR1) signaling is a potent solution for rheumatoid arthritis (RA). Herein, novel composite nucleic acid nanodrugs that simultaneously restrain TNF α binding and TNFR1 multimerization were designed to reinforce inhibition of TNF α-TNFR1 signaling for RA therapy. Towards this end, a novel peptide Pep4‐19 that suppresses TNFR1 clustering was extracted from TNFR1. The resulting peptide and a DNA aptamer Apt2‐55, which inhibits TNF α binding, were integrally or separately anchored on DNA tetrahedron (TD) to obtain nanodrugs with different spatial distribution of Apt2‐55 and Pep4‐19 (TD-3A-3P and TD-3(A-P)). Our results showed that Pep4‐19 enhanced the viability of inflammatory L929 cells. Both TD-3A-3P and TD-3(A-P) suppressed caspase 3, reduced cell apoptosis, and inhibited FLS-RA migration. Compared to TD-3(A-P), TD-3A-3P supplied sufficient flexibility for Apt2‐55 and Pep4‐19, and showed better anti-inflammation properties. Furthermore, TD-3A-3P significantly relieved symptoms in collagen-induced arthritis (CIA) mice, and the anti-RA efficacy through intravenous injection was comparable to transdermal administration via microneedles. Overall, the work provides an effective strategy for RA treatment by dual-targeting TNFR1, and demonstrates that microneedles are promising approach to drug administration in the treatment of RA.

Traditional Chinese Medicines (TCMs) have been used for centuries for the treatment and management of various diseases. However, their effective delivery to targeted sites may be a major challenge due to their poor water solubility, low bioavailability, and potential toxicity. Nanocarriers, such as liposomes, polymeric nanoparticles, inorganic nanoparticles and organic/inorganic nanohybrids based on active constituents from TCMs have been extensively studied as a promising strategy to improve the delivery of active constituents from TCMs to achieve a higher therapeutic effect with fewer side effects compared to conventional formulations. This review summarizes the recent advances in nanocarrier-based delivery systems for various types of active constituents of TCMs, including terpenoids, polyphenols, alkaloids, flavonoids, and quinones, from different natural sources. This review covers the design and preparation of nanocarriers, their characterization, and in vitro/vivo evaluations. Additionally, this review highlights the challenges and opportunities in the field and suggests future directions for research. Nanocarrier-based delivery systems have shown great potential in improving the therapeutic efficacy of TCMs, and this review may serve as a comprehensive resource to researchers in this field. [ABSTRACT FROM AUTHOR]

Background: Hypoxia, a common characteristic of the tumour microenvironment, is involved in tumour progression and immune evasion. Targeting the hypoxic microenvironment has been implicated as a promising antitumour therapeutic strategy. TH-302 can be selectively activated under hypoxic conditions. However, the effectiveness of TH-302 in gastric cancer combined immunotherapy remains unclear. Methods: We designed mPEG-PLGA-encapsulated TH-302 (TH-302 NPs) to target the hypoxic area of tumour tissues. A particle size analyzer was used to measure the average size and zeta potential of TH-302 NPs. The morphology was observed by transmission electron microscopy and scanning electron microscopy. The hypoxic area of tumour tissues was examined by immunofluorescence assays using pimonidazole. Flow cytometry analysis was performed to measure the levels of TNF-α, IFN-γ, and granzyme B. The synergistic antitumour activity of the combination of TH-302 NPs with anti-PD-1 (α-PD-1) therapy was assessed in vitro and in vivo. Haematoxylin and eosin staining of major organs and biochemical indicator detection were performed to investigate the biological safety of TH-302 NPs in vivo. Results: TH-302 NPs inhibited the proliferation and promoted the apoptosis of gastric cancer cells under hypoxic conditions. In vitro and in vivo experiments confirmed that TH-302 NPs could effectively alleviate tumour hypoxia. TH-302 NPs exhibited high bioavailability, effective tumour-targeting ability and satisfactory biosafety. Moreover, the combination of TH-302 NPs with α-PD-1 significantly improved immunotherapeutic efficacy in vivo. Mechanistically, TH-302 NPs reduced the expression of HIF-1α and PD-L1, facilitated the infiltration of CD8+ T cells and increased the levels of TNF-α, IFN-γ, and granzyme B in tumours, thereby enhancing the efficacy of α-PD-1 therapy. Conclusion: TH-302 NPs alleviated the hypoxic tumour microenvironment and enhanced the efficacy of PD-1 blockade. Our results provide evidence that TH-302 NPs can be used as a safe and effective nanodrug for combined immunotherapy in gastric cancer treatment. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix flooded with immune suppressive cells, resulting in extremely poor clinical response to immunotherapy. It has been revealed that the activation of pancreatic stellate cells (PSCs) makes considerable contributions to the immunological "cold" tumor microenvironment (TME). Herein, we developed a polyamino acid-based nanodrug incorporating the PSC activation inhibitor calcipotriol and anti-CXCL12 siRNA. The nanodrug was easily prepared with a small particle size and is capable of penetrating pancreatic tumors to inactivate PSCs and downregulate CXCL12. The in vivo results of orthotopic pancreatic tumor treatment demonstrated that codelivery of calcipotriol and anti-CXCL12 siRNA remodeled the PDAC TME with reduced extracellular matrix and decreased immunosuppressive T cells. Eventually, the infiltration of cytotoxic T cells was increased, thereby acting with immune checkpoint blockade (ICB) therapy for immunologically "cold" pancreatic tumors. In the present study, we propose a promising paradigm to improve the immunotherapy outcome of PDAC using nanodrugs that synchronously inhibit PSC activation and regulatory T-cell infiltration. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) that impedes the tumor infiltration of therapeutic agents and cytotoxic T lymphocytes, resulting in a poor clinical response to immunotherapy. In the present study, we proposed a promising approach for enhanced immunotherapy of pancreatic cancer. Specifically, a nanodrug incorporating calcipotriol and anti-CXCL12 siRNA was synthesized to synchronously inactivate matrix-producing pancreatic stellate cells and suppress the infiltration of regulatory T cells. The reduced ECM removed the pathological barrier, preventing nanodrug penetration and effector T-cell infiltration, leading to a conversion of the immunosuppressive "cold" microenvironment to a "hot" microenvironment, which eventually boosted the immunotherapy of anti-PD-1 antibodies in pancreatic cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Cell‐free therapy using conditioned medium (CM) from mesenchymal stem cells takes full advantage of the bioactive factors secreted by the cells while avoiding disadvantages such as immune rejection and tumor formation due to cell transplantation. In this study, human periodontal ligament stem cells (PDLSCs) are modified with the superparamagnetic iron oxide nanoparticle (SPION)‐based nanodrug ferumoxytol (PDLSC‐SPION). Compared with PDLSCs, PDLSC‐SPION showed good cell viability and better osteogenic differentiation ability. Cell‐free CM is collected and the anti‐inflammatory capacity of PDLSC CM and PDLSC‐SPION CM is assessed by treatment of lipopolysaccharide‐stimulated macrophages and IL‐17‐stimulated human gingival fibroblasts. Both CMs inhibited the expression of proinflammatory cytokines in cells, and the therapeutic effect is more distinct for PDLSC‐SPION CM than PDLSC CM, which may be due to their different proteomic compositions. Therefore, modification of PDLSCs with ferumoxytol enhances the anti‐inflammatory capacity of its CM, making it more potentially useful for the treatment of inflammatory diseases such as periodontitis. [ABSTRACT FROM AUTHOR]

The ambiguity of certain diseases and the potential toxicity of many medications have sparked demand for the incorporation and enhancement of drug delivery systems (DDSs). Nanomedicine has received renewed attention in modern medical advancements with therapeutic uses. Therefore, the development of nanomedicines for enhanced bioaccessibility, long drug administration, and dose reduction has advanced as a unique concept. Nanocapsules, nanoemulsions, drug nanocrystals, micelles, solid lipid nanoparticles (SLNs), and polymeric nanoparticles (poly-NPs) are among the most effective nanomedicine techniques. Poly-NPs have emerged as a potential method to enhance drug pharmacokinetics. Pharmaceutical potency can be increased by using nanocarriers and medication formulations. The potential of poly-NPs to alter contemporary medicine has attracted significant interest; polymer adaptability makes them suitable for site-specific drug delivery requirements. However, little is known about their safety in long-term studies using high-pitched doses. These cells exhibit some extrapyramidal symptoms (EPS) because of the reactivity and size reduction of the polymers chosen by using living cells other than the target. With an increased understanding of polymers and their properties, it is equally important to emphasize the safety and toxicity of DDSs. Some of the toxic effects of polymeric nanodrugs include an increase in the cytotoxicity of the cell, reduction in the feasibility of the cell, increase in the rate of programmed cell death (apoptosis), precursors for tumor formation, DNA destruction, gene toxicity, rupture of the cell membrane, and lipid peroxidation reactions. In this article, we discuss the toxicity of nanoparticles (NPs) used in DDSs, including polylactide-co-glycolide, polylactic acid, polycaprolactone, and poly-(alkyl cyanoacrylates), used in DDSs. [ABSTRACT FROM AUTHOR]

The integration of a multidimensional treatment dominated by active ingredients of traditional Chinese medicine (TCM), including enhanced chemotherapy and synergistically amplification of oxidative damage, into a nanoplatform would be of great significance for furthering accurate and effective cancer treatment with the active ingredients of TCM. Herein, in this study, we designed and synthesized four matrine-proteolysis-targeting chimeras (PROTACs) (depending on different lengths of the chains named LST-1, LST-2, LST-3, and LST-4) based on PROTAC technology to overcome the limitations of matrine. LST-4, with better anti-tumor activity than matrine, still degrades p-Erk and p-Akt proteins. Moreover, LST-4 NPs formed via LST-4 self-assembly with stronger anti-tumor activity and glutathione (GSH) depletion ability could be enriched in lysosomes through their outstanding enhanced permeability and retention (EPR) effect. Then, we synthesized LST-4@ZnPc NPs with a low-pH-triggered drug release property that could release zinc(II) phthalocyanine (ZnPc) in tumor sites. LST-4@ZnPc NPs combine the application of chemotherapy and phototherapy, including both enhanced chemotherapy from LST-4 NPs and the synergistic amplification of oxidative damage, through increasing the reactive oxygen species (ROS) by photodynamic therapy (PDT), causing an GSH decrease via LST-4 mediation to effectively kill tumor cells. Therefore, multifunctional LST-4@ZnPc NPs are a promising method for killing cancer cells, which also provides a new paradigm for using natural products to kill tumors.

Lung cancer (LC) is one of the leading causes of high cancer-associated mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common type of LC. The mechanisms of NSCLC evolution involve the alterations of multiple complex signaling pathways. Even with advances in biological understanding, early diagnosis, therapy, and mechanisms of drug resistance, many dilemmas still need to face in NSCLC treatments. However, many efforts have been made to explore the pathological changes of tumor cells based on specific molecular signals for drug therapy and targeted delivery. Nano-delivery has great potential in the diagnosis and treatment of tumors. In recent years, many studies have focused on different combinations of drugs and nanoparticles (NPs) to constitute nano-based drug delivery systems (NDDS), which deliver drugs regulating specific molecular signaling pathways in tumor cells, and most of them have positive implications. This review summarized the recent advances of therapeutic targets discovered in signaling pathways in NSCLC as well as the related NDDS, and presented the future prospects and challenges.

Introduction: Inflammatory bowel disease (IBD) affects about 7 million people globally, which is a chronic inflammatory condition of the gastrointestinal tract caused by gut microbiota alterations, immune dysregulation, genetic and environmental factors. Nanoparticles (NPs) deliver an active natural compound to a site harbored by disordered microbiota, they are used to interact, target and act intentionally on microbiota. Although there is accumulating evidence indicating that berberine and polysaccharide play an important role in IBD via regulating microbiota, there is limited research that presents a complete picture of exactly how their carrierfree co-assembled nanodrug affects IBD. Methods: The study establishes the carrier-free NPs formed by berberine and rhubarb polysaccharide based on the combination theory of Rheum palmatum L. and Coptis chinensis Franch., and characterizes the NPs. The IBD treatment efficacy of NPs are evaluated via IBD efficacy index, and explore the mechanism of NPs via 16S rRNA test and immunohistochemistry including occludin and zonula occludens-1. Results: The results showed that DHP and BBR were co-assembled to nanoparticles, and the BD can effectively relieve the symptoms of UC mouse induced by DSS via regulating gutmicrobiota and repair the gut barrier integrity, because BD have a longer retention on the colon tissue and react with the microbiota and mucus thoroughly. Interestingly, BD can enrich more probiotic than free BBR and DHP. Discussion: This design provides a better strategy and encourages future studies on IBD treatment via regulating gut microbiota and the design of novel plant polysaccharide based carrier-free co-assembly therapies. [ABSTRACT FROM AUTHOR]

Aging attenuates the overall responsiveness of the immune system to eradicate pathogens. The increased production of pro-inflammatory cytokines by innate immune cells under basal conditions, termed inflammaging, contributes to impaired innate immune responsiveness towards pathogen-mediated stimulation and limits antigen-presenting activity. Adaptive immune responses are attenuated as well due to lowered numbers of naïve lymphocytes and their impaired responsiveness towards antigen-specific stimulation. Additionally, the numbers of immunoregulatory cell types, comprising regulatory T cells and myeloid-derived suppressor cells, that inhibit the activity of innate and adaptive immune cells are elevated. This review aims to summarize our knowledge on the cellular and molecular causes of immunosenescence while also taking into account senescence effects that constitute immune evasion mechanisms in the case of chronic viral infections and cancer. For tumor therapy numerous nanoformulated drugs have been developed to overcome poor solubility of compounds and to enable cell-directed delivery in order to restore immune functions, e.g., by addressing dysregulated signaling pathways. Further, nanovaccines which efficiently address antigen-presenting cells to mount sustained anti-tumor immune responses have been clinically evaluated. Further, senolytics that selectively deplete senescent cells are being tested in a number of clinical trials. Here we discuss the potential use of such drugs to improve anti-aging therapy. [ABSTRACT FROM AUTHOR]

Abstract Macrophage polarization determines the production of cytokines that fuel the initiation and evolution of rheumatoid arthritis (RA). Thus, modulation of macrophage polarization might represent a potential therapeutic strategy for RA. However, coordinated modulation of macrophages in the synovium and synovial fluid has not been achieved thus far. Herein, we develop a biomimetic ApoA-I mimetic peptide-modified neutrophil membrane-wrapped F127 polymer (R4F-NM@F127) for targeted drug delivery during RA treatment. Due to the high expression of adhesion molecules and chemokine receptors on neutrophils, the neutrophil membrane coating can endow the nanocarrier with synovitis-targeting ability, with subsequent recruitment to the synovial fluid under the chemotactic effects of IL-8. Moreover, R4F peptide modification further endows the nanocarrier with the ability to target the SR-B1 receptor, which is highly expressed on macrophages in the synovium and synovial fluid. Long-term in vivo imaging shows that R4F-NM@F127 preferentially accumulates in inflamed joints and is engulfed by macrophages. After loading of the anti-inflammatory drug celastrol (Cel), R4F-NM@F127-Cel shows a significant reduction in hepatotoxicity, and effectively inhibits synovial inflammation and alleviates joint damage by reprogramming macrophage polarization. Thus, our results highlight the potential of the coordinated targeted modulation of macrophages as a promising therapeutic option for the treatment of RA.

Abstract Background Glioblastoma multiforme (GBM) is a fatal malignant primary brain tumor in adults. The therapeutic efficacy of chemotherapeutic drugs is limited due to the blood-brain barrier (BBB), poor drug targeting, and short biological half-lives. Multifunctional biomimetic nanodrugs have great potential to overcome these limitations of chemotherapeutic drugs. Methods We synthesized and characterized a biomimetic nanodrug CMS/PEG-DOX-M. The CMS/PEG-DOX-M effectively and rapidly released DOX in U87 MG cells. Cell proliferation and apoptosis assays were examined by the MTT and TUNEL assays. The penetration of nanodrugs through the BBB and anti-tumor efficacy were investigated in the orthotopic glioblastoma xenograft models. Results We showed that CMS/PEG-DOX-M inhibited cell proliferation of U87 MG cells and effectively induced cell apoptosis of U87 MG cells. Intracranial antitumor experiments showed that free DOX hardly penetrated the BBB, but CMS/PEG-DOX-M effectively reached the orthotopic intracranial tumor through the BBB and significantly inhibited tumor growth. Immunofluorescence staining of orthotopic tumor tissue sections confirmed that nanodrugs promoted apoptosis of tumor cells. This study developed a multimodal nanodrug treatment system with the enhanced abilities of tumor-targeting, BBB penetration, and cancer-specific accumulation of chemotherapeutic drugs by combining chemotherapy and photothermal therapy. It can be used as a flexible and effective GBM treatment system and it may also be used for the treatment of other central nervous systems (CNS) tumors and extracranial tumors.

Huaiji Wang,1,&ast; Zihan Zhao,2,&ast; Chenghao Wu,3,&ast; Xiaowen Tong,3 Yuling Shi,2 Shunjie Chen1 1Department of Nephrology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, 200443, People’s Republic of China; 3Department of Obstetrics and Gynecology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shunjie Chen, Department of Nephrology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China, Email chenshunjie77csj@163.comIntroduction: Transdermal drug delivery provides a desirable alternative method of penetrating the skin for psoriasis treatment, by virtue of its ability to dampen the overactivation of immune cells and inflammation, while attenuating the detrimental effects of systemic administration. Lymph nodes (LNs), as a critical organ of the lymphatic and the acquired immune system, are suitable sites for drug homing to suppress the immune cells.Methods: In this context, we developed a microneedle (MN) patch that delivers nanodrugs locally to LNs for improving the antipsoriatic treatment. In this study, human serum albumin nanoparticles carrying methotrexate (HM) were synthesized and loaded into hyaluronic acid (HA)-based microneedles (HM/MN).Results: The patch showed an excellent ability to pierce the skin, which enhanced drug delivery. In a mouse model of psoriasis, the HM/MN patch significantly prevented the erythema with decreased skin thickness, thus inhibiting the progression of psoriasis. Further analysis for immune cells in LNs, the percent of dendritic cells (DC) and T cells reduced after the local treatment with HM/MN. Notably, the feasibility of targeted delivery of methotrexate to LNs using nanoparticles was verified by detecting increased accumulation of methotrexate in LNs. In addition, the HM/MN patch pronouncedly decreased the levels of tumor necrosis factor α and interleukin 6 in the skin.Conclusion: The results suggested the high efficacy of using the HM/MN patch to treat psoriasis, and provided new insight into the mechanism of the transdermal drug delivery system.Keywords: microneedles, transdermal drug delivery, psoriasis, lymph node homing, nanodrug

Research and development (R&D) of nanodrugs is a long, complex and uncertain process. Since the 1960s, computing has been used as an auxiliary tool in the field of drug discovery. Many cases have proven the practicability and efficiency of computing in drug discovery. Over the past decade, computing, especially model prediction and molecular simulation, has been gradually applied to nanodrug R&D, providing substantive solutions to many problems. Computing has made important contributions to promoting data-driven decision-making and reducing failure rates and time costs in discovery and development of nanodrugs. However, there are still a few articles to examine, and it is necessary to summarize the development of the research direction. In the review, we summarize application of computing in various stages of nanodrug R&D, including physicochemical properties and biological activities prediction, pharmacokinetics analysis, toxicological assessment and other related applications. Moreover, current challenges and future perspectives of the computing methods are also discussed, with a view to help computing become a high-practicability and -efficiency auxiliary tool in nanodrugs discovery and development. [ABSTRACT FROM AUTHOR]

The dense extracellular matrix (ECM) is a key barrier to tumor infiltration of cytotoxic T lymphocytes (CTLs), which greatly compromises T cell-dependent immunotherapy of hepatocellular carcinoma (HCC). Herein, hyaluronidase (HAase), IL-12, and anti-PD-L1 antibody (αPD-L1) were co -delivered using a pH and MMP-2 dual-sensitive polymer/calcium phosphate (CaP) hybrid nanocarrier. The dissolution of CaP triggered by tumor acidity facilitated the release of IL-12 and HAase responsible for ECM digestion, enhancing the tumor infiltration and proliferation of CTLs. Furthermore, the in situ -released αPD-L1 inside tumor, as triggered by an overexpressed MMP-2, prevented the tumor cell from escaping the killing effects of CTLs. Such combination strategy induced a robust antitumor immunity for efficiently suppressing HCC growth in mice. Additionally, tumor acidity-sheddable polyethylene glycol (PEG) coating enhanced the tumor accumulation of nanocarrier and reduced the immune-related adverse events (irAEs) induced by on-target off-tumor αPD-L1. This dual-sensitive nanodrug demonstrates an effective immunotherapy paradigm for other dense ECM-characterized solid tumors. [Display omitted] • The extremely dense stromal prevents the infiltration of cytotoxic T lymphocytes. • Safe and efficient delivery of protein-based drugs is a management challenge. • Nanodrug depletes the hyaluronan to promote T-cell infiltration. • PEG shieldable nanodrug hide protein-based drugs in blood circulation to reduce side effects. [ABSTRACT FROM AUTHOR]

Affibody is a new class of small non-immunoglobulin affinity proteins that possesses high affinity at the picomole level to several tumor overexpressed receptors. Owing to the simple framework, affibody is flexible for modification with payload, but the relatively low molecular weight of this construction simultaneously results in short half-life time which hinders its application in cancer therapy. In this work, we prepared a nanomedicine self-assembled from the conjugate of affibody (ZPDGFRβ:09591, PDGFRβ: platelet-derived growth factor receptor β) with monomethyl auristatin E (MMAE) through cathepsin B cleavable dipeptide linker for targeted colorectal cancer therapy. The nanoscale characteristics of ZPDGFRβ:09591-MMAE affibody-drug conjugate nanomedicine (ZPDGFRβ:09591-M ADCN) resulted in enhanced pharmacokinetics, improved drug accumulation, and promoted biosecurity performance than those of free drugs. As a result, ZPDGFRβ:09591-M ADCN exhibited excellent antitumor efficacy with tumor inhibition rates (TIR) over 99.0% in PDGFRβ-positive tumor models with small solid tumors (∼ 150 mm3) or large established tumors (∼ 500 mm3), indicating that ZPDGFRβ:09591-MMAE ADCN is promising for the clinic application in colorectal cancer therapy. [ABSTRACT FROM AUTHOR]

Recently, Fenton reaction-mediated ferroptosis has attracted great attention in cancer treatment while the metabolism loss of iron and the limited endogenous H 2 O 2 level imped its clinical application. Here, a new ferroptosis inducer (Fe@cLANAs) constructed only by Fe(II) and (R)-(+)-lipoic acid (LA) was developed for tumor ablation. After entering the tumor cells, the Fe@cLANAs dissociated into disdihydrolipoic acid (DHLA) and released iron, which would regenerate each other to continuously provide iron and H 2 O 2 to enhance ferroptosis. The Fe@cLANAs demonstrated the IC 50 Fe below 10 μM against various tumor cells, an anti-tumor effect comparable to many chemotherapy drugs. In vivo antitumor evaluation based on the tumor cell-derived xenograft model showed a tumor inhibitory rate (TIR) of 97.4% at the iron usage of 1.53 mg/kg, the lowest iron usage reported so far in ferrotherapy using iron as the main agent to treat tumors. Notably, the good anti-tumor effect of Fe@cLANAs was further achieved in the glioma patient-derived xenograft (PDX) model. This strategy utilizing the reciprocal circulation of metal iron and LA to delay the metabolism loss of iron and increase the H 2 O 2 level in the tumor cells holds a great potential for ferroptosis-mediated cancer treatment. The metabolism loss of iron and the limited endogenous H 2 O 2 level are key factors to impede the clinical application of ferroptosis-mediated cancer treatment. Herein, a new ferroptosis inducer constructed only by lipoic acid and iron is developed to delay the metabolism loss of iron and increase the level of endogenous H 2 O 2 by causing a cyclic regeneration of Fe(II)/Fe(III) and LA/DHLA in the tumor cells. According to the previous reports, at least 75 mg/kg of iron dosage was needed to achieve effective antitumor efficacy, here, the use of only 1.53 mg/kg iron in Fe@cLANAs achieved the TIR of 97.4% and 62.8% in the U251 CDX and glioma PDX models, showing the good prospect of Fe@cLANAs in clinic. [Display omitted] [ABSTRACT FROM AUTHOR]

Treatments for osteosarcoma (OS) with pulmonary metastases reach a bottleneck with a survival rate of 10–20%. The suppressive tumor associated macrophages(TAMs) and CD47 over-expression greatly lead to the treatment failure. Sonodynamic therapy (SDT) can generate ROS with deep tumor penetration to induce tumor cell apoptosis, which is reported to further induce M1 macrophage polarization. CD47 inhibition combined with SDT to synergistically modulate TAMs may induce superior effects for OS treatment. In this work, for the first time, a biomimetic nanodrug named MPIRx was deveploped by loading IR780 (a sonosensitizer) and RRx-001 (a CD47 inhibitor) in PEG-PCL nanomicelles and then coating with OS cell membranes. After ultrasound activation, the nanodrug significantly inhibited OS proliferation and migration, induced apoptosis and immunogenic cell death in OS cells. Furthermore, MPIRx could guide macrophage migrating towards tumor cells and promote M1-type polarization while increasing the phagocytosis activity of macrophages on OS cells. Ultimately, MPIRx showed good tumor accumulation in vivo and successfully inhibited subcutaneous OS and orthotopic tumor with deterioration of pulmonary metastasis. Overall, by creating a local oxidative microenvironment and modulating the TAMs/CD47 in tumor tissue, the MPIRx nanodrug presents a novel strategy for macrophage-related immunotherapy to successfully eliminate OS and inhibit the intractable pulmonary metastasis. Construction and mechanism of MPIRx nanodrugs for CD47 immune checkpoint/sonodynamic therapy of osteosarcoma and lung metastasis. [Display omitted] • Sonodynamic therapy complements CD47 therapy in osteosarcoma mice model. • Sonodynamic therapy stimulate dual immunotherapy of macrophages and T cells. • Sonodynamic therapy combined with CD47 therapy improved survival of in situ OS-lung metastasis model. • The success of CD47 immunotherapy may greatly affected by the ROS of SDT. [ABSTRACT FROM AUTHOR]

Macrophage polarization determines the production of cytokines that fuel the initiation and evolution of rheumatoid arthritis (RA). Thus, modulation of macrophage polarization might represent a potential therapeutic strategy for RA. However, coordinated modulation of macrophages in the synovium and synovial fluid has not been achieved thus far. Herein, we develop a biomimetic ApoA-I mimetic peptide-modified neutrophil membrane-wrapped F127 polymer (R4F-NM@F127) for targeted drug delivery during RA treatment. Due to the high expression of adhesion molecules and chemokine receptors on neutrophils, the neutrophil membrane coating can endow the nanocarrier with synovitis-targeting ability, with subsequent recruitment to the synovial fluid under the chemotactic effects of IL-8. Moreover, R4F peptide modification further endows the nanocarrier with the ability to target the SR-B1 receptor, which is highly expressed on macrophages in the synovium and synovial fluid. Long-term in vivo imaging shows that R4F-NM@F127 preferentially accumulates in inflamed joints and is engulfed by macrophages. After loading of the anti-inflammatory drug celastrol (Cel), R4F-NM@F127-Cel shows a significant reduction in hepatotoxicity, and effectively inhibits synovial inflammation and alleviates joint damage by reprogramming macrophage polarization. Thus, our results highlight the potential of the coordinated targeted modulation of macrophages as a promising therapeutic option for the treatment of RA. [ABSTRACT FROM AUTHOR]

Cu-mediated chemodynamic therapy (CDT) has attracted prominent attention owing to its advantages of pH independence and high efficiency comparing to Fe-mediated CDT, while the application of Cu-based CDT agents was impeded due to the high copper consumption caused by the metabolism loss of copper and the resultant potential toxicity. Herein, we developed a new copper-mediated CDT agent with extremely low Cu usage by anchoring copper on cross-linked lipoic acid nanoparticles (Cu@cLAs). After endocytosis into tumor cells, the Cu@cLAs were dissociated into LA and dihydrolipoic acid (DHLA) (reduced form of LA) and released Cu2+ and Cu+ (oxidized form of Cu2+), the two redox couples recycled each other in cells to achieve the efficient killing of cancer cells by delaying metabolic loss and increasing the ROS level of tumor cells. The self-recycling was confirmed in cells by the sustained high Cu/DHLA content and persistent ROS generation process. The antitumor study based on the MCF-7/R nude mice gave the Cu@cLAs a tumor inhibitory rate up to 77.9% at the copper of 0.05 mg kg−1, the first dosage reported so far lower than that of normal serum copper (0.83 ± 0.21 mg kg−1). This work provides not only a new promising clinical strategy for the copper excessive use in copper-mediated CDT, but also gives a clue for other metal mediated disease therapies with the high metal consumption. [ABSTRACT FROM AUTHOR]

Abstract Background In the present study, the medicinal plants were exclusively selected based on their significant anti-HIV and anticancer activities. The green synthesis of gold nanoparticles was carried out using the 15 medicinal plant extracts on reduction with chloroauric acid. The present study also focused on a novel pharmacognostic approach over the usage of plants source. The nanoparticle synthesized through medicinal plants possessed the potential therapeutic properties of the plants. The resultant nanoparticle carried the attributes of a nanomaterial alongside the phytoactivity. Results Initially, individual nanoparticle (NP) was synthesized through a single plant extract and studied for its effective anti-HIV and anticancer activity. Finally, a nanoconjugate (NC) comprising of the 3 extracts (trio extract) in one nanoparticle was synthesized. The nanoparticles which exhibited comparatively high anti-HIV and anticancer activity were chosen for the synthesis of nanoconjugate, thereby achieving a synergistic anticancer and anti-HIV activity. Further, a nanodrug conjugate (NDC) was prepared in combination of AuNPs and the chemotherapeutic drug, doxorubicin (Dox) for cancer and AuNPs with antiretroviral drug azidothymidine (AZT) for HIV. Conclusions A nanodrug conjugate helps to enhance the efficiency of the drug. The nanodrug conjugate brings about a combinatorial effect of the nanomaterials and the drug. Further, a biocompatible nanocarrier was developed as a conjugate with chitosan and gold nanoparticles using STPP as gelating agent for the drug doxorubicin. The synthesis reaction was optimized under various underlying parameters. The gold nanoparticles proved to be stable at high temperature and different buffers and ensured to be a safe option for bioassays and in vivo applications. Upon storing the synthesized AuNPs at different storage conditions, the nanoparticles were observed to be highly stable for a period of more than 48 months. The present study resulted in biosynthesis of highly stable gold nanoparticles using medicinal plant extracts as reducing and stabilizing agents.

PD-L1 based targeting delivery of canagliflozin enables the multifaceted anti-tumor treatment. [Display omitted] • Canagliflozin inhibits cancer progression through co-suppressing of MAPK/ERK and PI3K/AKT signaling pathways. • Canagliflozin enhances the tumor immunotherapeutic efficacy by PD-L1 degradation. • Canagliflozin sensitizes to radiotherapy by decreasing DNA damage repair-related proteins. • PD-L1 targeted liposomal canagliflozin empowers the multimodal synergistic cancer therapy. Immunotherapy-involved combination cancer therapy heralds an unstoppable revolution in clinical practice. However, designing a streamlined approach to integrate immunotherapy with other therapies remains a formidable challenge. Canagliflozin, a clinical drug for type II diabetes, has gained growing interest in cancer therapy, albeit its precise mechanism remains largely elusive. Here, we delve into the multifaceted antitumor mechanisms of canagliflozin, including co-suppression of MAPK/ERK and PI3K/AKT signaling pathways, induction of PD-L1 degradation via ubiquitination and sensitization to X-ray irradiation via downregulation of DNA damage repair-related molecules, thereby offering opportunities for synergistic cancer treatment. For this purpose, we designed a universal nanoliposome coated with a PD-L1-targeting peptide to efficiently deliver canagliflozin in vivo. This simple fabricated nanodrug exhibited specific tumor-targeting ability and excellent biosafety. In vivo anti-cancer efficacy evaluation revealed synergistic pathway-targeted therapy from canagliflozin and immunotherapy facilitated by both canagliflozin and peptide. Furthermore, the introduction of radiotherapy further augmented the overall treatment performance. This study will revisit the diverse anti-tumor mechanisms of canagliflozin and its potential in cancer therapy, greatly expanding its clinical indication. In addition, the targeted delivery system of canagliflozin developed in this study will achieve multimodal synergistic cancer therapy, providing solutions to challenges in clinical cancer treatment and beyond. [ABSTRACT FROM AUTHOR]

Sympathetic nerves play a pivotal role in promoting tumor growth through crosstalk with tumor and stromal cells. Chemotherapy exacerbates the infiltration of sympathetic nerves into tumors, thereby providing a rationale for inhibiting sympathetic innervation to enhance chemotherapy. Here, we discovered that doxorubicin increases the density and activity of sympathetic nerves in breast cancer mainly by upregulating the expression of nerve growth factors (NGFs) in cancer cells. To address this, we developed a combination therapy by co-encapsulating small interfering RNA (siRNA) and doxorubicin within breast cancer-targeted poly (lactic- co -glycolic acid) (PLGA) nanoparticles, aiming to suppress NGF expression post-chemotherapy. Incorporating NGF blockade into the nanoplatform for chemotherapy effectively mitigated the chemotherapy-induced proliferation of sympathetic nerves. This not only bolstered the tumoricidal activity of chemotherapy, but also amplified its stimulatory impact on the antitumor immune response by increasing the infiltration of immunostimulatory cells into tumors while concurrently reducing the frequency of immunosuppressive cells. Consequently, the combined nanodrug approach, when coupled with anti -PD-L1 treatment, exhibited a remarkable suppression of primary and deeply metastatic tumors with minimal systematic toxicity. Importantly, the nanoplatform relieved chemotherapy-induced peripheral neuropathic pain (CIPNP) by diminishing the expression of pain mediator NGFs. In summary, this research underscores the significant potential of NGF knockdown in enhancing immunochemotherapy outcomes and presents a nanoplatform for the highly efficient and low-toxicity treatment of breast cancer. [ABSTRACT FROM AUTHOR]

It is imperative to optimize chemotherapy for heightened anti-tumor therapeutic efficacy. Unrestrained tumor cell proliferation and sustained angiogenesis are pivotal for cancer progression. Plinabulin, a vascular disrupting agent, selectively destroys tumor blood vessels. Tirapazamine (TPZ), a hypoxia-activated prodrug, intensifies cytotoxicity in diminishing oxygen levels within tumor cells. Despite completing Phase III clinical trials, both agents exhibited modest treatment efficiency due to dose-limiting toxicity. In this study, we employed methoxy poly(ethylene glycol)- b -poly(D, L -lactide) (mPEG- b -PDLLA) to co-deliver Plinabulin and TPZ to the tumor site, concurrently disrupting blood vessels and eliminating tumor cells, addressing both symptoms and the root cause of tumor progression. Plinabulin was converted into a prodrug with esterase response (PSM), and TPZ was synthesized into a hexyl chain-containing derivative (TPZHex) for effective co-delivery. PSM and TPZHex were co-encapsulated with mPEG- b -PDLLA, forming nanodrugs (PT-NPs). At the tumor site, PT-NPs responded to esterase overexpression, releasing Plinabulin, disrupting blood vessels, and causing nutritional and oxygen deficiency. TPZHex was activated in response to increased hypoxia, killing tumor cells. In treating 4T1 tumors, PT-NPs demonstrated enhanced therapeutic efficacy, achieving a 92.9 % tumor suppression rate and a 20 % cure rate. This research presented an innovative strategy to enhance synergistic efficacy and reduce toxicity in combination chemotherapy. A "two-pronged" combined therapeutic strategy for treating tumors by integrating the destruction of tumor blood vessels and blocking unlimited cell proliferation could potentially offer a comprehensive therapeutic effect, akin to eradicating the tumor at its roots. This scheme was created with BioRender.com. [Display omitted] [ABSTRACT FROM AUTHOR]

Although the survival rate of hematological malignancies (HM) has increased in recent years, the unnecessary adverse effect to the body is usually generated by the traditional chemotherapy for HM due to the lack of specificity to tumor tissue. Nanodrug delivery systems have exhibited unique advantages in targetability, stability and reducing toxicity, attracting wide concern, which is expected to be the prevalent alternative for the treatment of HM. In this review, we systemically introduced the current therapeutic strategies and the categories of HM. Subsequently, five key factors including circulation, targeting, penetration, internalization and release involving in tailoring nanoparticles were demonstrated, followed by the introduction of the development of nanodrug delivery—traditional synthetic nanomaterilas, biomimetic cell membrane coating nanomaterials, cell-based nanomaterials as well as immunotherapy combined with nanodrug. Afterwards, the recent advances of nanodrug delivery system for the treatment of HM were introduced. Moreover, the challenge and prospect of nanodrug delivery system in treating HM were discussed. The promising drug delivery system will provide new therapeutic avenues for the treatment of HM. [ABSTRACT FROM AUTHOR]

Folate receptors (FRs) are overexpressed on activated macrophages in inflammatory diseases. In this regard, the FRs-targeting strategy is a good option for the diagnosis and treatment of macrophage-mediated diseases. Here, we developed FRs-targeted nanomaterials that specifically deliver the anti-atherogenic drug lobeglitazone into macrophage foam cells via a strong binding affinity to FRs. The prepared FRs-targetable nanodrug is nontoxic to macrophage foam cells and efficiently delivers lobeglitazone into macrophage foam cells via the FRs-mediated endocytosis. Consequently, the FRs-targetable nanodrug significantly decreases the formation of foam cells by inhibiting the accumulation of lipid droplets in macrophage foam cells. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) can induce cancer cell death through hydroxyl radicals (·OH) generated from Fenton or Fenton-like reactions. Compared with traditional therapies, CDT effectively overcomes inevitable drug resistance and exhibits low side effects. However, clinical application still faces challenges, primarily due to insufficient ·OH generation and the short-lifetime of ·OH in vivo. To address these challenges, we developed a peroxynitrite (ONOO - )-based CDT nanodrug (DOX@PMOF) composed of MOF-199, NO donor (PArg), and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) activator (doxorubicin, DOX). In DOX@PMOF, MOF-199 serves as both a carrier for loading DOX and a source of Cu + for triggering CDT. Upon uptake by cancer cells, the high concentration of glutathione (GSH) reduces MOF-199 to Cu + , which then reacts with H 2 O 2 to generate ·OH. Moreover, the released DOX upregulates NOX4 expression, leading to the elevated H 2 O 2 level and thereby promoting a high-efficiency Fenton-like reaction for sufficient ·OH generation. Subsequently, PArg generates abundant NO in response to the tumor microenvironment, leading to a cascade of NO and ·OH for the in situ synthesis of ONOO - . ONOO - is more toxic and has a longer lifetime and diffusion distance than ·OH, resulting in a more effective CDT treatment. To further enhance the in vivo therapeutic effect, we coated DOX@PMOF with a homologous cell membrane to form an active tumor-targeting nanodrug (DOX@MPMOF), which has demonstrated the ability to effectively inhibit tumor growth and metastasis while exhibiting good biosafety.