PDL1-driven self-amplifying drug homing with immune homeostasis restoration

Antibody-decorated nanomedicines can selectively deliver drugs to tumors. However, their targeting efficiency diminishes as the density of the target antigen decreases. To address this limitation, this study developed a PDL1-driven, self-sustaining feedback drug-homing nanoparticle, termed aPDL1-PLG-DOX nanoparticles (aPDL1-P-DOX). This construction was prepared by loading doxorubicin (DOX) into a phenylboronic acid-bearing poly( _L -glutamic acid) carrier responsive to reactive oxygen species (ROS) through boron-nitrogen coordination, followed by conjugation with an anti-PDL1 monoclonal antibody (aPDL1). The aPDL1 moiety directs nanoparticles to PDL1-expressing tumors, where elevated ROS levels trigger DOX release. In turn, residual tumor cells upregulate PDL1 expression in response to DOX, thereby enhancing subsequent recruitment of aPDL1-P-DOX and establishing a self-sustaining tumor-selective drug delivery cycle. This feedback-induced mechanism not only increases the specificity and persistence of DOX accumulation in tumors but also leverages co-delivered aPDL1 to mitigate DOX-associated immunosuppression and restore immune homeostasis. In a murine colon cancer model, this strategy achieved 98.7% inhibition of tumor growth and significantly prolonged survival, representing a promising approach for durable and precise cancer therapy.