MMP-9–responsive stealth-to-activation liposomes enable tumor-selective PD-L1 degradation via dual-PEG shedding

Abstract

Abstract PD-1/PD-L1 blockade benefits patients across > 20 cancer types, yet durable responses remain limited and antibody therapies only transiently engage the axis while causing systemic immune-related adverse events. We report lipoRDPA, a rationally designed liposomal degrader that fuses MMP-9-responsive gating with PD-L1-targeted protein degradation (TPD) into a single unified mechanism. The platform conjugates anti-PD-L1 antibody atezolizumab (DPA) onto a liposome and shields it with an MMP-9-cleavable PEG cloak, so that PD-L1 binding, internalization, and lysosomal degradation are activated only in the protease-rich TME while staying silent in circulation. Crucially, the MMP-9 gate and the degrader form one mechanism: unlike classical enzyme-gated carriers that cleave to release an entrapped payload, the cloak is the switch that confines an intrinsically active degradation effector to the tumor—the central challenge of nanobody-targeted protein degradation. In vitro, lipoRDPA exhibits PD-L1-dependent binding and degrades both surface and total PD-L1 through targeted degradation, circumventing receptor recycling and ligand competition to sustain T-cell activation beyond blockade. In vivo imaging confirms reduced off-target distribution and enriched tumor accumulation. In human-T-cell-reconstituted NSG mice, lipoRDPA enhances intratumoral CD8⁺ T-cell infiltration, suppresses Ki-67, and yields the strongest tumor growth inhibition. In immunocompetent BALB/c mice, the murine counterpart lipoRDPa similarly inhibits tumors while preserving normal lung PD-L1 and avoiding the pulmonary inflammation seen with constitutively exposed formulations. By fusing TME-gated activation with a PD-L1-targeted degrader into one tumor-gated mechanism, lipoRDPA confines checkpoint elimination to the tumor, reconciling antitumor efficacy with tissue-level biosafety and providing a generalizable strategy for tumor-gated targeted protein degradation immunotherapy.