Liver fibrosis is a prevalent liver disease associated with significant morbidity, and the activation of hepatic stellate cells (HSCs) serves as the primary causative factor driving the progression of liver fibrosis. However, capillarization of liver sinusoidal endothelial cells (LSECs) induced by hepatic fibrosis can reduce nitric oxide (NO) production and bioavailability, which consequently loses the ability to retain HSCs dormant, leading to amplified HSCs activation. Herein, an elaborate micelle (VN-M@BN) loaded with benazepril (BN) was constructed by self-assembly of polymeric NO donor, aiming for the controlled release of NO in liver fibrosis lesions thereby impeding the progression of liver fibrosis. VN-M@BN with the vitamin A (VA) ligand modification was designed to target HSCs for efficient liver fibrosis inhibition. Controlled NO release significantly downregulated α-smooth muscle actin (α-SMA) and induced apoptosis of activated HSCs, thus enhancing the inhibition effects of BN towards HSCs. Furthermore, the in suit antifibrotic treatment results confirmed that VN-M@BN possessed good circulatory stability and targetability to liver fibrotic tissues, thereby effectively ameliorating the collagen deposition and fibrosis process in damaged liver tissues. The NO-based targeted nanodrug system enabled precise delivery of therapeutic drugs to activated HSCs, thereby synergizing the efficacy in treating liver fibrosis with minimal adverse effects.

Bacteria-infected chronic wound is one of the most serious complications of diabetes and characterized with high morbidity and risk of lower extremity amputation. Nitric oxide (NO) represents a promising strategy to accelerate wound healing through down-regulating inflammation, promoting angiogenesis and bacterial eradication. However, stimuli-responsive and control release of NO at the wound microenvironment remains a challenge. In this work, an injectable, self-healing and antibacterial hydrogel characterized with glucose-responsive and constant NO release behaviors has been engineered for diabetic wound management. The hydrogel (CAHG) is prepared by in situ crosslinking of L-arginine (L-Arg)-coupled chitosan and glucose oxidase (GOx)-modified hyaluronic acid based on Schiff-base reaction. The system is capable of mediating a continuous release of hydrogen peroxide (H2O2) and NO by the cascaded consumption of glucose and L-Arg in the presence of hyperglycemia environment. In vitro studies demonstrate that bacteria proliferation is significantly inhibited by CAHG hydrogel involving in the cascaded release of H2O2 and NO. More importantly, a full-thickness skin wound model on a diabetic mouse demonstrates that H2O2 and NO release from CAHG hydrogel exhibits a superior efficiency for wound healing through bacterial inhibition, down-regulation of pro-inflammatory factors and the elevation of M2-type macrophage, contributing to the collagen deposition and angiogenesis. In conclusion, CAHG hydrogel with excellent biocompatibility and glucose-responsive NO release characteristic can serve as a highly efficient therapeutic strategy for diabetic wound treatment.

Immune checkpoint blockade (ICB) has achieved breakthrough in the area of oncotherapy by relieving immunosuppression of T cells and eliciting durable antitumor responses. However, the ICB therapy remains extremely challenging because of low tumor immunogenicity and immunosuppressive tumor micro-environment (ITME). Herein, a NIR-triggered nitric oxide (NO)-releasing nano-gasholder (denoted as UNTPs) is developed to combine with ICB therapy for reprogramming ITME and enhancing immune ther-apeutic effects. This NO-releasing nano-gasholder is composed of upconversion nanoparticles (UCNPs) core stabilzied by biodegradable polymeric NO-donor of poly(ethylene glycol)-poly(nitrate carbonate)-pen-taethylenehexamine copolymer (mPEG-PNTC-PEI). NO release from the UNTPs nano-gasholder is ac-celerated by the ultraviolet (UV)-stimulation, which is converted from UCNPs core upon the NIR irradiation. The instantaneous NO burst exerts direct tumor killing by the strong reactive ability and significantly sti-mulates immunogenic cell death (ICD) of tumor cells, thereby promoting the maturation of dendritic cells (DCs) and the infiltration of T cells. Furthermore, the ITME is remodeled into an immunostimularoty milieu through the inhibition of the PD-L1 expression and the polarization of tumor-associated macrophages (TAMs) into antitumor M1 phenotype by a large amount of NO, and ICB of anti-PD-1 antibody (alpha PD-1), leading to impressive primary tumor shrinkage, efficient distant tumor inhibition and long-term survival.(c) 2022 Elsevier Ltd. All rights reserved.

Mitoxantrone (MTO) is clinically utilized for treating hormone-refractory prostate cancer (PCa), however, the therapeutic outcome is far from optimal due to the lack of proper drug carrier as well as the inherent MTO detoxification mechanisms of DNA lesion repair and anti-oxidation. Herein, a bombesin-installed nanoplatform combining the chemotherapeutic MTO and the chemotherapeutic sensitizer of nitric oxide (NO) is developed based on MTO-loaded macromolecular NO-donor-containing polymeric micelles (BN-NMMTO ) for targeted NO-sensitized chemotherapy against PCa. BN-NMMTO actively target and accumulates in PCa sites and are internalized into the tumor cells. The macromolecular NO-donor of BN-NMMTO undergoes a reductive reaction to unleash NO upon intracellular glutathione (GSH), accompanying by micelle swelling and MTO release. The targeted intracellular MTO release induces DNA lesion and reactive oxygen species (ROS) generation in tumor cells without damage to the normal cells, and MTO's cytotoxicity is further augmented by NO release via the inhibition of both DNA repair and anti-oxidation pathways as compared with traditional MTO therapies.

The lack of tumor immunogenicity coupled with the presence of tumor immunosuppression severely hinders antitumor immunity, especially in the treatment of "immune cold" tumors. Here, we have developed a drug-free and NIR-enabled nitric oxide (NO)-releasing nanogasholder (NOPS@BP) composed of an outer cloak of nitrate-containing polymeric NO donor and an inner core of black phosphorus (BP) as the energy converter to spatiotemporally regulate NO-mediated tumor microenvironment remodeling and achieve multimodal therapy. Following NIR-irradiation, BP-induced photothermia and its intrinsic reducing property accelerate NO release from the outer cloak, by which the instantaneous NO burst concomitant with mild photothermia, on the one hand, induces immunogenic cell death (ICD), thereby provoking antitumor responses such as the maturation of dendritic cells (DCs) and the infiltration of cytotoxic T lymphocytes (CTLs); on the other hand, it reverses tumor immunosuppression via Treg inhibition, M2 macrophage restraint, and PD-L1 downregulation, further strengthening antitumor immunity. Therefore, this drug-free NOPS@BP by means of multimodal therapy (NO gas therapy, immune therapy, photothermal therapy) realizes extremely significant curative effects against primary and distant tumors and even metastasis in B16F10 tumor models, providing a new modality to conquer immune cold tumors by NO-potentiated ICD and immunosuppression reversal.