A Nano‐Isolation Strategy for Tumor‐Activatable Photodynamic Therapy via Aggregation‐Gated Type I Photosensitizers

Abstract

ABSTRACT Photodynamic therapy (PDT) is hampered by high oxygen dependence and off‐target phototoxicity, and existing tumor‐activatable strategies are severely plagued by the aggregation‐induced reactive oxygen species (ROS) quenching post‐activation. We herein resolve these challenges through pioneering a smart “nano‐isolation” strategy, synergized with aggregatin‐induced emission (AIE)‐hemicyanine (Hcy) photosensitizers with an aggregation‐gated ROS generation feature. Propelled‐type AIE motifs were introduced to planar Hcy derivatives to construct twisted donor‐π‐acceptor photosensitizers, among which MTPAON with the largest conformational twist exhibited the best AIE effect and the highest ROS generation, predominantly generating less oxygen‐dependent type I ROS. Crucially, MTPAON's ROS generation is gated by aggregation degree, where only tightly packed aggregates activate ROS generation. Leveraging this, we pioneered a “nano‐isolation” strategy by encapsulating MTPAON in glutathione (GSH)‐responsive nanoparticles at a high polymer ratio (SSPEG‐7 NPs). This nano‐isolation initially suppresses MTPAON's tight aggregation and silences ROS generation. Upon encountering tumor‐overexpressed GSH, SSPEG‐7 NPs disassemble and release MTPAON to form type I ROS‐competent aggregates in tumor cells. SSPEG‐7 NPs thus demonstrated promising antitumor performance under low‐dose laser irradiation, while exhibiting negligible off‐target phototoxicity to normal tissues. This “nano‐isolation” strategy establishes a new paradigm for precision PDT: leveraging stimulus‐triggered aggregation to spatially control PDT activation, thereby reconciling the conflict between systemic safety and therapeutic potency.