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

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.