β-Galactosidase-Cleavable Polymeric Senotherapeutics for Protein-Binding Photodynamic Senolysis

Selective elimination of senescent cells (SnCs) through senolytic strategies can counteract the progression of age-related dysfunction, but achieving precise, broad-spectrum, and controllable senolysis remains challenging. Here, we report PG@FBC, a polymeric senotherapeutic that exploits senescence-associated β-galactosidase (SA-β-gal) to trigger supramolecular disassembly and controlled photosensitizer release, enabling photodynamic senolysis with real-time imaging. Briefly, PG@FBC is composed of an amphiphilic block copolymer, POEGMA-b-GMA (PG), synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization from hydrophilic POEGMA and SA-β-gal-cleavable hydrophobic β-GMA units. Subsequent coassembly of PG with FBC photosensitizer affords core-shell nanoparticles featuring a hydrophobic core and a hydrophilic shell, with preferential uptake by SnCs. Once localized within SnCs, overexpressed SA-β-gal cleaves the β-GMA units of PG@FBC, triggering disassembly and releasing FBC. The released FBC binds intracellular proteins to mitigate aggregation-caused quenching (ACQ), enhance solubility, and amplify ROS generation under NIR-irradiation, inducing senolysis with minimal off-target cytotoxicity. In addition, the intrinsic fluorescence of FBC provides real-time imaging capability, establishing PG@FBC as a precise theranostic platform for integrated monitoring and elimination of SnCs in senescence-associated pathologies.