Enzyme‐Triggered Disassembly of Perylene Monoimide‐based Nanoclusters for Activatable and Deep Photodynamic Therapy

Photodynamic therapy (PDT) exhibits great potential for cancer therapy, but still suffers from nonspecific photosensitivity and poor penetration of photosensitizer. Herein, a smart perylene monoimide‐based nanocluster capable of enzyme‐triggered disassembly is reported as an activatable and deeply penetrable photosensitizer. A novel carboxylesterase (CE)‐responsive tetrachloroperylene monoimide (P1) was synthesized and assembled with folate‐decorated albumins into a nanocluster (FHP) with a diameter of circa 100 nm. Once P1 is hydrolyzed by the tumor‐specific CE, FHP disassembles into ultrasmall nanoparticles (ca. 10 nm), facilitating the deep tumor penetration of FHP. Furthermore, such enzyme‐triggered disassembly of FHP leads to enhanced fluorescence intensity (ca. 8‐fold) and elevated singlet oxygen generation ability (ca. 4‐fold), enabling in situ near‐infrared fluorescence imaging and promoted PDT. FHP permits remarkable tumor inhibition in vivo with minimal side effects through imaging‐guided, activatable, and deep PDT. This work confirms that this cascaded multifunctional control through enzyme‐triggered molecular disassembly is an effective strategy for precise cancer theranostics. Things fall apart: A smart perylene monoimide‐based nanocluster (FHP) capable of enzyme‐triggered disassembly is reported as an activatable nano‐photosensitizer. FHP disassembles into circa 10‐nm nanoparticles, simultaneously leading to deep tumor penetration, enhanced fluorescence intensity (ca. 8‐fold), and elevated singlet oxygen generation (ca. 4‐fold).