Biomimetic gold nano-modulator for deep-tumor NIR-II photothermal immunotherapy via gaseous microenvironment remodeling strategy

Introduction Effective immunotherapeutic treatment of solid tumors has been greatly challenged by the complex hostile tumor immunosuppressive microenvironment (TIME), which typically involves hypoxia and immunosuppression. Methods Herein, a multifunctional biomimetic gold nano-modulator (denoted as GNR-SNO@MMT ) was developed to realize the efficient second near-infrared (NIR-II) photothermal immunotherapy via tumor targeting and deep penetration, vascular normalization and immune reprogramming. NIR-II photothermal agent gold nanorods (GNR) were grafted with thermosensitive S-nitrosothiol (SNO) donors and camouflaged with the tumor-penetrating peptide tLyp-1-modified macrophage membrane (MM) to yield GNR-SNO@MMT . Results The engineered membrane coating increased the capacity for tumor inflammatory tropism and deep penetration, which aided GNR-SNO@MMT in ablating tumors together with NIR-II laser irradiation. Moreover, hyperthermia-stimulated nitric oxide (NO) release in situ acted as a gas immunomodulator to effectively enhance blood perfusion and reprogram the TIME via multiple functions (e.g., decreasing PD-L1, repolarizing tumor-associated macrophages, and revitalizing cytotoxic T cells). Ultimately, the inhibition rate against 4T1 mouse mammary tumor model mediated by GNR-SNO@MMT plus NIR-II laser was 94.7% together with 2.4-fold CD8 + T cells infiltrated into tumors than that of the untreated counterpart. Conclusions The engineered biomimetic nano-modulator of GNR-SNO@MMT provides an effective and novel photoimmunotherapy candidate against deep-sited solid tumors through immune reconfiguration via NO-involved nanomedicine and external NIR-II laser assistance. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12951-025-03304-2.