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

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.