A Sonochemically Activatable Pro‐Molecular Glue for Spatiotemporally Controlled Targeted Protein Degradation

ABSTRACT Molecular glues offer a powerful paradigm for targeting undruggable proteins, yet their clinical translation is frequently impeded by on‐target, off‐tumor toxicities. Developing activatable strategies for molecular glues remains a formidable challenge due to their compact, featureless scaffolds that resist chemical modification. Herein, we report a sonochemically activatable pro‐molecular glue strategy for spatiotemporally controlled targeted protein degradation. By identifying the critical aniline group, a structural linchpin for neosubstrate recruitment, as the optimal caging site, we rationally designed a pro‐lenalidomide (PL) equipped with a singlet oxygen ( 1 O 2 )‐cleavable self‐immolative linker. This prodrug is co‐assembled with a semiconducting polymer (SP) sonosensitizer to construct an activatable nanoplatform. Upon ultrasound irradiation, the in situ‐generated 1 O 2 functions as a precise chemical switch, triggering the oxidative cleavage of the linker to uncage the molecular glue within the tumor microenvironment. This “off‐to‐on” capability orchestrates a potent antitumor response by synergizing sonodynamic stress with reinstated IKZF1/3 degradation. Uniquely, this strategy confines pharmacological activity strictly to the tumor site, thereby eliciting robust therapeutic efficacy while broadening the therapeutic window. This work establishes a generalizable chemical toolkit for designing activatable molecular glues, paving the way for safer precision cancer therapies.