用于胃癌治疗中奥沙利铂级联递送的MMP响应性含TAT的聚合物胶束

Abstract

Although nanodrug delivery systems have advanced cancer therapy, limited tumor penetration and inefficient intracellular transport still restrict their therapeutic efficacy. Herein, we constructed a matrix metalloproteinase (MMP)-responsive, TAT-containing polymeric micelle, O@MTPP, for cascade delivery of oxaliplatin in gastric cancer. O@MTPP integrates an MMP-2/9-cleavable peptide, MTP (GPLGIAG), with the cell-penetrating and nuclear-localization-associated TAT peptide (CYGRKKRRQRRR). In the tumor microenvironment, MMP-2/9-mediated cleavage triggers charge conversion, enhancing tumor-cell internalization and penetration-associated distribution. After cellular uptake, TAT further promotes nuclear-associated accumulation of the nanocarrier-associated payload, supporting improved intracellular delivery of oxaliplatin. This cascade delivery strategy enhanced tumor accumulation, strengthened antitumor activity, and induced immunogenic cell death (ICD)-associated immune responses, including calreticulin exposure, high mobility group box 1 (HMGB-1) expression, increased tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-12 (IL-12) levels, and decreased interleukin-6 (IL-6). Overall, O@MTPP provides an enzyme-activated cascade delivery strategy for overcoming tissue-level and intracellular barriers in oxaliplatin-based gastric cancer therapy.