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.

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.

The therapeutic potential of nitric oxide (NO) has been highly attractive to tumor treatment, especially for surmounting the multidrug resistance (MDR) of cancer. However, the NO-involved therapy remains extremely challenging because of the difficulty to simultaneously control the NO release rate and real-time concentration. Herein, we construct NO-containing polymersomes with high amount of NO donors inherently grown on the polymer chains to keep the stability. These polymersomes can be simultaneously loaded with photosensitizer of IR780 iodide on the membrane layer and chemotherapeutic of DOX·HCl in the lumen. NO release can be triggered by the reduction conditions, and further accelerated by remote NIR irradiation due to the increased local temperature. The instantaneous NO release with high concentration significantly inhibits the P-gp expression and sensitize the chemotherapy, thus overcoming the tumor MDR and improving the anti-tumor activity. Meanwhile, DOX·HCl release is highly promoted at the intracellular conditions because of the cleavage of acid-labile cis-aconitic amide at endo/lysosomal pH, and the improved hydrophilicity of the membrane layer after NO release. The in vivo results show that the single intravenous injection of polymersome formulation companying with NIR irradiation exerts multi-modal therapies of chemotherapy, PTT/PDT, and NO-therapy on the MCF-7/R tumor models, showing superior and combinational treatment efficacy with the complete eradication of tumors and few side effects.

We report that active substance (CPUL1) and triphenylphosphine (TPP) derivative could self-assemble into multifunctional nanoaggregates (CPUL1-TPP NAs) through electrostatic and pi-pi stacking interactions. CPUL1 was wrapped tightly inside the nanoparticles as well as CPUL1 and TPP derivative self-assembled into stable and compact nanoparticles in water. The positive surface charge of CPUL1-TPP NAs made them much easier to be endocytosed to enter cytoplasm, accumulate in the mitochondria and induce cell apoptosis based on their mitochondria targeting ability, fluorescence property and fast cell uptake characteristic, which showed better antitumor efficacy on HUH7 hepatoma cells in vitro than that of free CPUL1.