Anti-Protein-Adsorption Nano-Proteolysis Targeting Chimeras as a Potent Platform for Efficient Programmed Cell Death Ligand 1 Degradation.

Abstract

Immune checkpoint blockade (ICB) therapies targeting the PD-1/PD-L1 axis have shown clinical promise, yet most patients do not achieve durable responses due to adaptive PD-L1 upregulation and recycling. While nanoparticle-based proteolysis targeting chimeras (PROTACs) offer a strategy for direct PD-L1 degradation, their therapeutic potential remains largely untapped because of a fundamental barrier: the inevitable formation of a nonspecific protein corona that severely limits target engagement. Here, we introduce a corona-free nano-PROTACs platform (CF-nPTs) that overcomes this obstacle. By integrating DSPE-PCB─a zwitterionic antifouling amphiphile with exceptional resistance to protein adsorption─into micellar nano-PROTACs, we construct a nano-PROTACs system capable of maintaining an ultraclean surface in biological fluids. Compared with previously reported Au, liposomal, and micellar based nano-PROTACs platforms, the CF-nPTs effectively resisted nonspecific protein adsorption, markedly enhanced the corecruitment of PD-L1 and E3 ligase, and enabled highly efficient proteasome-mediated PD-L1 degradation. Additionally, the corona-free architecture also promoted robust lymph-node targeting, further amplifying immunotherapeutic efficacy. As a result, CF-nPTs achieved pronounced tumor regression, extended survival, and strong immune activation in both subcutaneous melanoma and lymph-node-metastasis models. Collectively, this study identifies protein-corona resistance as a key determinant of nano-PROTACs performance and establishes CF-nPTs as a promising platform for efficient target protein degradation.