MMP-Responsive TAT-Containing Polymeric Micelles for Cascade Delivery of Oxaliplatin in Gastric Cancer Therapy

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.