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Bioact. Mater., Available online 3 April 2026 | https://doi.org/10.1016/j.bioactmat.2026.03.049 AdMSC spheroids encapsulating antioxidant hybrid protein carrier for irradiation-damaged salivary gland repair

Byulhana Kim ^{a b 1}, Hyerin Yoo ^{c 1}, Young Ju Son ^d, Seyun Ahn ^{a b}, Jeonghoon Lee^c, Young Kim ^b, Tae Hee Kim ^e, Min Rye Eom ^d, Young Bin Choy ^{a f g h i}, Justin J. Chung^{b f j *}, Seong Keun Kwon^{c d k l m n *}

^aInterdisciplinary Program in Bioengineering, College of Engineering, Seoul National University, Seoul, 08826, Republic of Korea
^bDepartment of Transdisciplinary Medicine, Seoul National University Hospital, Seoul, 03080, Republic of Korea
^cInterdisciplinary Program in Stem Cell Biology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
^dDepartment of Otorhinolaryngology-Head and Neck Surgery, Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea
^eDepartment of Fusion Research and Collaboration, Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea
^fInnovative Medical Technology Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea
^gDepartment of Clinical Medical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
^hInstitute of Medical and Biological Engineering, Medical Research Center, Seoul National University, Seoul, 03080, Republic of Korea
ⁱDepartment of Biomedical Engineering, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
^jDepartment of Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
^kDepartment of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea
^lDepartment of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, 03080, Republic of Korea
^mCancer Research Institute, Seoul National University, Seoul, 03080, Republic of Korea
ⁿSensory Organ Research Institute, Seoul National University Medical Research Center, Seoul, 03080, Republic of Korea

¹These authors contributed equally

^*Corresponding authors: correspondence to Justin J. Chung or Seong Keun Kwon

Abstract

Radiation therapy for head and neck cancer often causes xerostomia, a chronic salivary gland (SG) dysfunction driven by excessive reactive oxygen species (ROS), severely impacting the quality of life of patients. Existing treatments, such as artificial saliva or SG stimulants, offer only temporary relief. We developed a novel therapeutic system combining glutathione (GSH)-conjugated gelatin (Gel) hybrid protein-based cell carrier (GC) with adipose-derived mesenchymal stem cell (AdMSC) spheroids. This hybrid protein carrier (GC) extended the antioxidant activity of GSH by overcoming its short half-life and enabled efficient encapsulation and delivery of AdMSC spheroids to irradiation (IR)-damaged SGs. The 3D spheroids enhanced vascular endothelial growth factor (VEGF) expression through hypoxic core formation, promoting angiogenesis. In an IR-damaged mouse model, spheroid-encapsulated GC increased SOD2 expression and decreased 8-OHdG and NOX4 levels, effectively mitigating oxidative stress, fibrosis, and apoptosis, while accelerating angiogenesis. SG structural regeneration and functional recovery were confirmed using histological and immunohistochemical analyses following spheroid-encapsulating GC treatment. These results demonstrate the synergistic effects of ROS-scavenging activity from GC and paracrine signaling from AdMSC spheroids. This groundbreaking spheroid-encapsulating GC improves SG regeneration and functional recovery by integrating antioxidant activity with angiogenic effects, offering a paradigm-shifting solution for other oxidative stress-mediated tissue disorders.

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