Rational Designof PROTAC Degraders and Their SpatiotemporalControlled Delivery for Enhanced Tumor Penetration and PD-L1 ProteinDegradation

Abstract While immune checkpoint blockade technologies targeting PD-1/PD-L1 have revolutionized cancer therapy, conventional small-molecule inhibitors are still limited by their occupancy-driven mechanisms and require sustained high-dose exposure, which exacerbates off-target toxicity. To overcome this, we developed cyclic iRGD peptide-engineered PROTAC nanoparticles (iRP NPs) for precise PD-L1 degradation. This delivery system integrates three major modules: (1) the rationally designed PROTAC (CL-F-B1), which optimizes the E3 ligase/PD-L1 binding domain spatial relationship to efficiently trigger PD-L1 ubiquitination (achieving 67.05% degradation at 5 μM over 24 h); (2) the tumor-penetrating iRGD peptide, binding αvβ3 integrins and inducing neuropilin-1-mediated transcytosis for deep tumor penetration; and (3) self-assembled NPs, prolonging circulation and stabilizing the construct. In the MC38 colon cancer model, iRP NPs demonstrated superior tumor-specific accumulation and PD-L1 degradation, achieving 80.88% tumor regression. This strategy of coupling targeted degradation with smart delivery offers an efficient, precise, and accessible pathway for immune checkpoint modulation.