Cascade-driven nanomotor with self-amplifying necrosis targeting and deep tumor penetration for enhanced type I photodynamic immunotherapy

Cancer cells adjacent to the necrotic regions within deep-seated tumors exhibit elevated metastatic potential, while photodynamic immunotherapy, which utilizes photosensitizers as triggers to exert synergistic effects of photodynamic therapy (PDT) and anti-tumor immunotherapy, has attracted considerable interest. However, high oxygen dependency and complex biological barriers hinder the efficacy of nanomedicines by restricting reactive oxygen species generation and intratumoral penetration. Herein, a laser-triggered nanomotor (HCAT NPs) with self-amplifying necrosis targeting and deep tumor penetration is prepared for enhanced type I photodynamic immunotherapy. HCAT NPs can accumulate at the tumor site <i>via</i> targeting necrotic tissues, while recovered fluorescence emitted from hypericin can be used to self-monitor drug distribution and optimize laser exposure timing. Excitingly, Cu²⁺ significantly enhances type I photosensitivity of hypericin by facilitating electron transfer and glutathione depletion, while cascade reactions triggered by the type I PDT induce the generation of nitric oxide, which synergistically promotes deep tumor penetration with hypericin <i>via</i> nanomotor propulsion and remodels vascular networks. Notably, the activated fluorescence emitted from TPE-4NM is utilized to self-report the generation of nitric oxide, while TPE-4NMB can eliminate peroxynitrite, which is related to tumor metastasis. The well-designed HCAT NPs demonstrate potent phototherapy effects against primary breast tumors, recurrences, and distant metastases, providing insight into the development of type I photosensitizers and novel cascade reaction-driven precision strategies for deep tumor ablation.