Low-Density Lipoprotein-Mimetic Nanoparticles Codelivering Self-Activated Cabazitaxel Prodrug and Verteporfin for Tumor Chemophotodynamic Therapy and Immune Activation

Abstract

Cabazitaxel (CTX) exhibits potent antineoplastic activity and is demonstrated to promote antitumor immunity by triggering immunogenic cell death (ICD). This is commonly used in the clinical treatment of advanced and metastatic triple-negative breast cancer (TNBC). However, the therapeutic index of commercial CTX injections is severely restricted by their definite systemic toxicity and low tolerability. Herein, we developed biomimetic low-density lipoprotein nanoparticles (CTX2TK&VP@LDL NPs) by integrating ROS-responsive CTX dimeric prodrugs (CTX2TK) and the photosensitizer verteporfin (VP) into LDL NPs to selectively target tumors and achieve synergistic chemophotodynamic therapy and immunotherapy for TNBC with improved biosafety. CTX2TK&VP@LDL NPs were able to enhance the accumulation and cellular uptake in 4T1 tumors overexpressing LDL receptor, improving the targeted codelivery efficiency. When CTX2TK&VP@LDL NPs were deposited at the tumor sites, localized 1O2 was generated upon irradiation for triggering ultrafast CTX release with low premature CTX leakage in the off-target tissue. Additionally, the generated 1O2 can further synergistically reinforce ICD and elicit robust antitumor immune activation. The combination treatment with CTX2TK&VP@LDL NPs and PD-L1 blockade notably inhibited abscopal tumor growth and lung metastasis. Taken together, the biomimetic CTX2TK&VP@LDL NPs exploit endogenous LDL functionality to enable receptor-mediated tumor targeting and synergistic chemophotodynamic immune activation, providing an effective and safe therapeutic strategy for TNBC.