A Bifunctional Lysosome‐Targeting Chimera Nanoplatform for Tumor‐Selective Protein Degradation and Enhanced Cancer Immunotherapy

Abstract Lysosome‐targeting chimeras (LYTACs) have recently emerged as a promising therapeutic strategy for degrading extracellular and membrane‐associated pathogenic proteins by hijacking lysosome‐targeting receptors. However, the antitumor performance of LYTAC is limited by its insufficient tumor accumulation and nonspecific activation. Additionally, the synergistic effects of LYTACs and other therapeutic modalities are crucial. To address these issues, a bifunctional LYTAC nanoplatform (NLTC) is developed for tumor‐selective protein degradation and enhanced cancer immunotherapy. By rationally controlling the surface composition, the NLTC can effectively transport extracellular or membrane proteins into lysosomes for degradation via cation‐independent mannose 6‐phosphate receptors. With removable surface modification, an NLTC is obtained that efficiently accumulated in tumor tissues and avoided on‐target off‐tumor toxicity. Moreover, the synthesis method of NLTC is generally applicable to various enzymes. Thus, catalase (CAT) is encapsulated with NLTC to synergistically degrade cancer cell surface programmed death ligand‐1 (PD‐L1), relieve the immunosuppressive tumor microenvironment for effective cancer immunotherapy, and significantly inhibit tumor growth, recurrence, and metastasis in B16F10‐bearing mice. This work presents a bifunctional LYTAC nanoplatform that can not only perform tissue‐selective protein degradation but also integrate other therapeutic modalities, providing insights into the design of advanced LYTAC technologies for clinical applications.