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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.<\/jats:p>","DOI":"10.1021\/acsbiomaterials.6c00489","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T16:59:42Z","timestamp":1779382782000},"page":"3493-3511","source":"Crossref","is-referenced-by-count":1,"title":["Engineered GelMA Microgels for Locoregional Doxorubicin Release and Apoptosis Induction in Oral Squamous Cell Carcinoma"],"prefix":"10.1021","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5476-6755","authenticated-orcid":true,"given":"Rajat","family":"Dadheech","sequence":"first","affiliation":[{"name":"Indian Institute of Technology Guwahati , , , , ,","place":["Guwahati, Assam, India, 781039"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3955-6618","authenticated-orcid":true,"given":"Manikumar","family":"Kodieswaran","sequence":"additional","affiliation":[{"name":"Indian Institute of Technology Guwahati , , , , ,","place":["Guwahati, Assam, India, 781039"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3936-4621","authenticated-orcid":true,"given":"Biman B.","family":"Mandal","sequence":"additional","affiliation":[{"name":"Indian Institute of Technology Guwahati , , , , ,","place":["Guwahati, Assam, India, 781039"]},{"name":"Indian Institute of Technology Guwahati , , , , ,","place":["Guwahati, Assam, India, 781039"]},{"name":"Indian Institute of Technology Guwahati , , , , ,","place":["Guwahati, Assam, India, 781039"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"issue":"1","key":"2026101319075715800_cit1","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","article-title":"Head and neck squamous cell carcinoma","volume":"6","author":"Johnson","year":"2020","journal-title":"Nat. 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