2. Academic Validation
  3. Metformin glycyrrhetinic acid binary injectable hydrogel for synergistic tumor immunotherapy via spatiotemporal microenvironment remodeling

Metformin glycyrrhetinic acid binary injectable hydrogel for synergistic tumor immunotherapy via spatiotemporal microenvironment remodeling

  • Mater Today Bio. 2025 Dec 27:36:102749. doi: 10.1016/j.mtbio.2025.102749.
Alu Ouyang 1,  Xin Qin 1,  Bo Su 1,  Shaojuan Mo 1,  Jiujun Jiang 1,  Zixin Wang 1,  Yu Li 1,  Jiayu Lu 1,  Yangzheng Lin 2,  Jie Wang 1,  Ling Fan 3,  Ronghua Jin 1
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Guangxi Key Laboratory of Pharmaceutical Precision Detection and Screening, and Key Laboratory of Micro-Nanoscale Bioanalysis and Drug Screening of Guangxi Education Department, Pharmaceutical College, Guangxi Medical University, Nanning, 530021, China.
  • 2 Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, 528401, China.
  • 3 Guangxi key laboratory of Chemistry and Engineering of Forest Products, State Ethnic Affairs Commission, Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi Collaborative Innovation Center for Chemistry and Engineering of Forest Products, School of chemistry and chemical engineering, Guangxi Minzu University, Nanning, 530006, China.
PMID: 41560796 DOI: 10.1016/j.mtbio.2025.102749
Abstract

The immunosuppressive tumor microenvironment, orchestrated by tumor cells through multifaceted immune evasion mechanisms, presents a significant challenge to the coordinated regulation of immunocytes. To overcome these limitations, we synthesized metformin glycyrrhetinic acid salt (Met-GA), which exhibits a 189-fold increase in anti-tumor potency compared to free metformin. An injectable Met-GA hydrogel (Met-GA-H) was formed through a "heating-cooling" cycling. To enable in situ gelation at the tumor site, Fe3O4 NPs were incorporated into the Met-GA suspension. This combination leverages Fe3O4 NPs-mediated photothermal triggering to achieve in situ gelation while enabling multitiered immune cell reprogramming, resulting in a multifunctional hydrogel designated as Fe3O4 NPs@Met-GA-H. This Fe3O4 NPs@Met-GA-H not only induced immunogenic cell death (ICD), as evidenced by a 4.7-fold increase in extracellular ATP, a 1.5-fold upregulation of calreticulin (CRT) exposure, and a 1.5-fold downregulation of high-mobility group box 1 (HMGB1), but also promoted M1 macrophage polarization (2.3-fold increase compared to control) and downregulated PD-L1 expression (2.8-fold decrease compared to control). It enables synergistic modulation of tumor cells, macrophages, and T lymphocytes within a unified platform. Quantitative biodistribution analysis showed a 13.0-fold higher tumor retention on day 7 post-administration compared to the free drug. The Fe3O4 NPs@Met-GA-H demonstrated robust immunotherapeutic efficacy in vivo through sustained ICD activation, macrophage reprogramming, immune checkpoint reactivation, and enhanced infiltration of cytotoxic T lymphocytes. This work establishes a regulatory-compliant precision immunotherapy paradigm based on the rational design of FDA-approved components, achieving synchronized spatiotemporal control over tumor-immune interactions.

Keywords

Immune checkpoint blockade; Immunogenic cell death; Injectable hydrogel; Melanoma; Metformin glycyrrhetinic acid salts.

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