Nanoscale Acid-Activated Peptide Platform That Reprograms Autophagy to Potentiate Oral Cancer Chemotherapy

Oral squamous cell carcinoma (OSCC) is a common malignancy for which traditional chemotherapy is limited by severe systemic toxicity and insufficient drug accumulation because of the complex tumor microenvironment. A key factor driving poor clinical outcomes is protective autophagy, an adaptive survival mechanism utilized by tumor cells to resist therapeutic intervention. Here, we modified the PHSCN peptide to design an amphiphilic peptide, DR/Pep1, which self-assembles into spherical nanoparticles to codeliver doxorubicin (DOX) and rapamycin (RAPA). DR/Pep1 enables significantly greater drug uptake by CAL-27 cells, activates apoptosis, and effectively inhibits cell migration. Notably, DR/Pep1 initiates autophagy by damaging DNA while simultaneously amplifying autophagic flux by inhibiting mTORC1, causing a shift from protective autophagy to lethal autophagy. This results in autophagy-dependent cell death (ADCD) that substantially inhibits OSCC cell proliferation and angiogenesis. Importantly, the nanoscale conformation of Pep1 changes in the acidic tumor environment, markedly increasing the intratumoral drug concentration and leading to a high tumor suppression rate. Our findings demonstrate that the targeted modulation of autophagy from a prosurvival to a death-inducing mechanism represents a promising strategy for increasing chemotherapeutic efficacy in the context of oral squamous cell carcinoma (OSCC). This nanoscale platform is well suited for OSCC therapy because the acid-triggered morphological transformation of the surface-engineered peptide nanoplatform allows deep tumor penetration.