Up-converted nano-gasholder with precise nitric oxide release remodels immunosuppressive microenvironment and potentiates tumor immunotherapy

•UNTPs composed of biodegradable polymeric NO-donor with the cooperation of UCNPs as the energy converter•Direct tumor killing by the strong reactive ability of the abundant NO upon NIR-irradiation•NO-induced tumor immunogenic cell death (ICD) to promote occurrence of DCs maturation and intratumoral infiltration of CTLs•Tumor immunosuppressive microenvironment modulation by NO burst to down-regulate PD-L1 and polarize macrophages from M2 to M1•UNTPs+L+αPD-1 by cooperative therapies of NO and ICB to realize primary and distant tumor inhibition with little side effect [Display omitted] Schematic illustration of the construction and NIR-regulated NO releasing procedure for up-converted polymeric NO-stabilized nano-gasholder (UNTPs), and the proposed workflow of UNTPs upon NIR-irradiation to inhibit the primary and distant tumors by leveraging the benefits of NO as an immunomodulatory molecule and combinig with immune checkpoint blockade. 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 microenvironment (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 therapeutic 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)-pentaethylenehexamine copolymer (mPEG-PNTC-PEI). NO release from the UNTPs nano-gasholder is accelerated 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 stimulates 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 (αPD-1), leading to impressive primary tumor shrinkage, efficient distant tumor inhibition and long-term survival.