Self-assembly prodrugs for controlled singlet oxygen release and resistance modulation in deep-tumor photodynamic therapy

Abstract

Photodynamic therapy (PDT) offers spatiotemporally controlled tumor ablation via photosensitizer-mediated singlet oxygen (¹O₂) generation, yet its application to deep-seated solid tumors remains fundamentally constrained by limited light penetration and tumor hypoxia. Endoperoxides (EPOs), which reversibly capture and release ¹O₂, offer a promising strategy to overcome these constraints. Nevertheless, existing EPO-based systems suffer from uncontrolled half-life-dependent ¹O₂ release and inefficient utilization. Moreover, PDT-induced oxidative stress upregulates inducible nitric oxide synthase (iNOS), leading to nitric oxide (NO) overproduction that quenches ¹O₂ and promote adaptive resistance. Herein, we report a self-assembly nano-prodrug enabling on-demand ¹O₂ release while suppressing NO-mediated resistance. An amphiphilic prodrug, L-NARG-SS-Py, comprising a ¹O₂-storing pyridone moiety and an iNOS inhibitor linked via a glutathione-responsive disulfide bond, co-assembles with protoporphyrin IX to form nano-prodrug (PPIX@L-NARG-SS-Py NPs). Upon irradiation, generated ¹O₂ is captured and stored as EPO intermediates, followed by glutathione-triggered release in tumor microenvironment. Simultaneously, released iNOS inhibitor suppresses NO production, thereby reducing ¹O₂ quenching and amplifying oxidative damage. In deep-seated pancreatic tumor models, the nano-prodrug achieves potent tumor suppression with minimal systemic toxicity. This work establishes a biologically amplified, light-independent PDT strategy for overcoming physical and adaptive resistance in deep-tissue phototherapy.