Phase-Transition Nanoparticles Enable Fluorescence Self-Reporting for Close-Loop Photodynamic Therapy

Photodynamic therapy (PDT) faces a fundamental limitation of the intrinsic energy utilization competition between fluorescence and reactive oxygen species (ROS) generation, while conventional "open-loop" protocols with pre-determined irradiation parameters risk overtreatment damage. To circumvent both challenges, we herein report phase transition nanoparticles (PTNPs) that enable self-regulated, self-reported, close-loop PDT via switching photosensitizers' molecular conformation. PTNPs were fabricated by co-encapsulating a twisted intramolecular charge transfer-aggregation-induced emission (TICT-AIE) photosensitizer (OTPA-DCPP) and the phase-change material n-docosane (C22, T_m ≈ 44.4 °C) into lipid-PEG nanoparticles. With TICT effect to reduce the singlet-triplet energy gap and AIE effect to suppress nonradiative dissipation, OTPA-DCPP exhibits polarity-enhanced type I ROS generation. C22 initially creates a rigid and polar microenvironment that stabilizes OTPA-DCPP's TICT and AIE effects, maximizing ROS generation. During PDT progress, PTNPs consumed oxygen and accumulated heat, the melted C22 above T_m created a nonpolar microenvironment, restoring the intense fluorescence while halting ROS generation. The emerged fluorescence serves as a real-time indicator of OTPA-DCPP's functional status, providing an unambiguous cue to cease irradiation to avoid energy waste and excessive heat buildup. As such, PTNPs circumvent excited-state energy reallocation challenges, which also serve as a self-reported, close-loop PDT system for safe and precise phototheranostics.