Rational Design of PROTAC Degraders and Their Spatiotemporal Controlled Delivery for Enhanced Tumor Penetration and PD-L1 Protein Degradation

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.