Engineered GelMA Microgels for Locoregional Doxorubicin Release and Apoptosis Induction in Oral Squamous Cell Carcinoma

Localized chemotherapeutic delivery remains a critical unmet need in head and neck squamous cell carcinoma (HNSCC), where the systemic administration of chemotherapeutics such as doxorubicin is constrained by rapid clearance, low tumor retention, and dose-limiting toxicities. These challenges necessitate more effective, less invasive drug-delivery platforms to improve therapeutic outcomes and patient well-being. In this study, we engineered photocrosslinked gelatin methacrylate (GelMA) microgels via a water-in-oil emulsion approach as an injectable, biodegradable platform for sustained locoregional doxorubicin delivery (Dox@GelMA microgels). These microgels exhibited spherical morphology, tunable swelling behavior, enzyme-responsive degradability, and high drug-loading efficiency, enabling prolonged, controlled drug release. Dox@GelMA microgels exerted significant cytotoxicity on KB and CAL 33 oral cancer cells by elevating reactive oxygen species levels, inducing DNA damage, and arresting the cell cycle in the S-phase, ultimately leading to apoptosis. To recapitulate the intricate tumor microenvironment, a silk-fibroin-based 3D oral squamous cell carcinoma (OSCC) model was established to augment physiologically relevant validation of localized chemotherapy by enabling peritumoral microgel application. Notably, Dox@GelMA microgels activated intrinsic apoptosis in the 3D models by upregulating Bax and p53 gene expression while decreasing Bcl-2 levels. These findings position bioengineered GelMA microgels as a minimally invasive, translationally promising approach to overcome the limitations of systemic chemotherapy in HNSCC.