Ultrasound Guided Local Delivery of Bioorthogonal PDL1 Degrader for Enhanced Immunotherapy

Abstract Immunotherapy involving PDL1 degradation holds great potential in anti‐tumor treatment. Optimal design of PDL1 degraders and subsequent efficient delivery into tumors are essential for expected efficacy, especially when abnormal tumor vasculature is considered. Herein, a nanodroplet‐based novel drug delivery platform termed as NDs^mTx (nanodroplet‐based therapeutics) for ultrasound targeted delivery of PDL1 degrader is designed. Briefly, the shell of the NDs^mTx is armed with RGD and mPD1 (a bioorthogonal PD1 mutant produced by genetic codon expansion technology can covalently bind PDL1), and the core is composed of perfluorohexane (PFH, C6F14). The RGD on the NDs^mTx recognizes αvβ3 expressed by tumor vasculature, making NDs^mTx accumulated in tumor practical and visible by low‐frequency ultrasound (LFUS). In turn, inertial cavitation induced by LFUS facilitates mPD1 on the nanodroplet debris penetrating the tumor, where mPD1 covalently binds PDL1 and initiates a lysosomal degradation process. Through both in vitro and in vivo study, the superior performance of NDs^mTx in degrading PDL1 and boosting anti‐tumor immunity is confirmed. In conclusion, NDs^mTx emerge as an alternative to existing PDL1 blockers in tumor immunotherapy.