Nano-in-Micro GelMA depots assist electro-thermal-immuno orchestral treatment for solid triple negative breast tumor

Jiachen Li; Yaping Zhuang; Huijie Han; Yuewen Zhu; Chao Lin; Rui Wang; Ana Catarina Rodrigues da Silva; Marc C A Stuart; Guimei Jiang; Siyu Fan; Romana Schirhagl; Mohammad-Ali Shahbazi; Lígia Raquel Marona Rodrigues; Wenguo Cui; Hélder A Santos

doi:10.1016/j.mtbio.2026.102848

Nano-in-Micro GelMA depots assist electro-thermal-immuno orchestral treatment for solid triple negative breast tumor

Mater Today Bio. 2026 Jan 30:37:102848. doi: 10.1016/j.mtbio.2026.102848. eCollection 2026 Apr.

Authors

Jiachen Li^{1

2}, Yaping Zhuang¹, Huijie Han^{2

3}, Yuewen Zhu², Chao Lin^{1

4}, Rui Wang^{1

5}, Ana Catarina Rodrigues da Silva^{2

6

7}, Marc C A Stuart⁸, Guimei Jiang¹, Siyu Fan², Romana Schirhagl², Mohammad-Ali Shahbazi², Lígia Raquel Marona Rodrigues^{6

7}, Wenguo Cui¹, Hélder A Santos^{2

1}

Affiliations

¹ Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China.
² Department of Biomaterials and Biomedical Technology, The Personalized Medicine Research Institute (PRECISION), University Medical Center Groningen, University of Groningen, Groningen, 9713 AV, the Netherlands.
³ College of Chemistry and Life Science, Beijing University of Technology, 100 Pingleyuan, Chaoyang District, Beijing, 100124, China.
⁴ Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214000, China.
⁵ The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
⁶ CEB-Centre of Biological Engineering, Universidade do Minho, Campus de Gualtar, Braga, 4710-057, Portugal.
⁷ LABBELS, Associate Laboratory, Braga, Guimarães, Portugal.
⁸ Groningen Biomolecular Sciences and Biotechnology Institute, Faculty of Science and Engineering, University of Groningen, Nijenborgh 7, Groningen, 9747 AG, the Netherlands.

Abstract

Triple-negative breast cancer (TNBC) exhibits high local-recurrence risk despite modern systemic therapy assisted with surgery or irradiation therapy. Here, we report an injectable nano-in-micro microsphere depot (cPAG) that integrates conductivity enhancement, photothermal conversion, O₂ and reactive oxygen species (ROS) generation, and innate immune agonist co-delivery to support staged, local multimodal therapy. Monodispersed Au@GelMA microspheres prepared via microfluidics and photocrosslinking reduced high electrostatic resistance of GelMA hydrogels and provided stable 808 nm laser-responsive heating. The porous surface possessed abundant electrostatic adsorption sites for loading MnO_x nanoflowers and anionic stimulator of interferon genes (STING) agonist. MnO_x nanoflowers catalyzed H₂O₂ to generate O_2, produced free radical signals and increased pro-inflammatory cytokines secretion in vitro. Co-delivery of agonist and MnO_x nanoparticles further increased interferon-β secretion, consistent with induction of type I interferon response. In a 4T1 residual-tumor model established by partial tumor resection, a staged regimen consisting of cPAG-assisted irreversible electroporation followed by cPAG-mediated photothermal therapy showed the strongest suppression of local tumor regrowth among tested groups, with maintained body weight during the study window. Overall, cPAG provides a modular nano-in-micro depot strategy to integrate multiple local treatments for postoperative control of TNBC tumor.

Keywords: Combination therapy; Local treatments; Microsphere depot; Nano-in-Micro; TNBC.