Cancer Cell Membrane-Coated Homodimer Prodrug Nanoassemblies to Simultaneously Deliver Prodrugs and Immune Adjuvants for Combined Chemo-Immunotherapy
Yingjie Zhao, Tian Liu, Yi Wang, Lingxiao Li, Xue Lin, Wenjing Wang, Jingzhe Sheng, Mengyu Liu, Dongchun Liu, Zhonggui He, Bingjun Sun, Yuki Takahashi, Jin Sun
Abstract
Homodimer prodrug nanoassemblies (HPNAs) gain significant attention due to their ultrahigh drug-loading capacity and carrier-free nature but suffer from poor self-assembly stability and rapid clearance from blood circulation. Cell membranes prove as a promising coating material for nanoparticle modification, offering specialized properties such as specific recognition, prolonged circulation time, and immune evasion. Here, we present a cancer cell membrane-modified biomimetic nanoassembly system designed for combined chemo-immunotherapy. We design a paclitaxel dimer-based small-molecule self-assembling prodrug, PTX-STeS-PTX (PSTeSP). The biomimetic nanoassemblies are constructed by using R848/PSTeSP nanoassemblies (RPNAs) to create a nanocore with an outer layer modified by cancer cell membranes (CCM), abbreviated as CCM-coated RPNAs (RP@CCM NAs). The CCM modification improves the stability of RPNAs in blood circulation and increases their accumulation at tumor sites. Additionally, CCM-coated RPNAs exhibit enhanced homologous targeting specificity toward cancer cells, significantly promoting cellular uptake and selectively inducing cytotoxicity in tumor cells. Furthermore, the incorporation of R848 into the PSTeSP-based nanoassemblies enhances the immune complexity at tumor sites, reshapes the tumor immune microenvironment, and inhibits cancer cell metastasis, enabling a combined chemotherapy and immunotherapy approach. This study explores the potential of CCM as a surface modification material to enhance the pharmacokinetic profile and tumor-specific targeting of HPNAs, offering a rational strategy for HPNA-based drug delivery systems in effective cancer treatment.