Abstract 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.
Zhang et al. (Mon,) studied this question.