Abstract
Therapeutic efficacy against solid tumors is limited by physical barriers and immunosuppressive tumor microenvironments (TME). Herein, we propose a peroxynitrite (ONOO−) overproduction-based strategy to simultaneously disrupt tumor barriers and activate antitumor immunity. A spatiotemporally controllable ONOO− nanogenerator (PNO-Y@M) was constructed by co-encapsulating hypericin within nitric oxide (NO)-donor polymeric nanoparticles coated with homologous tumor cell membranes. Upon laser irradiation, PNO-Y@M enables in-situ ONOO− generation via the coupling of photodynamically generated superoxide anions and photothermally triggered NO release. The resulting ONOO− effectively degrades extracellular matrix components and normalizes tumor vasculature, thereby enhancing nanoparticle penetration. Meanwhile, it induces immunogenic cell death, promoting dendritic cell maturation and M1 macrophage polarization, and ultimately activating robust adaptive immunity. This strategy significantly increased cytotoxic and helper T cell infiltration and induced strong immune memory in-vivo, leading to effective tumor suppression and metastasis inhibition. Overall, this work provides a promising strategy for overcoming the dual barriers of solid tumors through coordinated physical disruption and immune activation.
