A microsphere-vesicle hybrid system for tumor treatment through enhancement of innate and adaptive immune responses

Yida Chen; Xinyi Cheng; Can Zhu; Mimi Chen; Yi Wang; Chang Liu; Jie Sun; Hao Shen; Junjie Niu; Huilin Yang; Xingzhi Liu; Wenguo Cui; Qin Shi

doi:10.1016/j.biomaterials.2025.123587

A microsphere-vesicle hybrid system for tumor treatment through enhancement of innate and adaptive immune responses

Biomaterials. 2026 Feb:325:123587. doi: 10.1016/j.biomaterials.2025.123587. Epub 2025 Jul 28.

Authors

Yida Chen¹, Xinyi Cheng¹, Can Zhu¹, Mimi Chen², Yi Wang¹, Chang Liu¹, Jie Sun¹, Hao Shen¹, Junjie Niu¹, Huilin Yang¹, Xingzhi Liu³, Wenguo Cui⁴, Qin Shi⁵

Affiliations

¹ Department of Orthopedics, The First Affiliated Hospital of Soochow University, Orthopedic Institute of Soochow University, Medical College of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215031, PR China.
² Department of Orthopedics, Children Hospital of Soochow University, No. 92 Zhongnan Street Suzhou, Jiangsu, 215000, PR China.
³ Central Laboratory, Ruijin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine, NO.149 South Chongqing Road, Shanghai, 200020, PR China. Electronic address: w617905296@163.com.
⁴ Central Laboratory, Ruijin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine, NO.149 South Chongqing Road, Shanghai, 200020, PR China; Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, PR China. Electronic address: wgcui80@hotmail.com.
⁵ Department of Orthopedics, The First Affiliated Hospital of Soochow University, Orthopedic Institute of Soochow University, Medical College of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215031, PR China. Electronic address: shiqin@suda.edu.cn.

PMID: 40763579
DOI: 10.1016/j.biomaterials.2025.123587

Abstract

Cancer immunotherapies, designed to modulate innate and/or adaptive immune responses alongside targeting immune checkpoint pathways, are hindered by the immunosuppressive properties of the tumor microenvironment (TME). In the present study, we developed a therapeutic system composed of TIM-3 antibody-loaded gelatin methacrylated (GelMA) microspheres conjugated with K7M2 osteosarcoma cell-derived vesicles containing EZH2 inhibitor EPZ6438 via an MMP2-responsive peptide sequence DPG. The hybrid system not only directly kills tumor cells and indirectly amplifies anticancer immunity, but also reprograms the TME by promoting tumor-associated macrophage polarization to the M1 phenotype, enhancing tumor-associated dendritic cell activation and blocking TIM-3-mediated immune suppression. Altogether, the engineered system releases both the drugs and antibodies to promote tumor apoptosis and reprograms the TME via modulation of innate and adaptive immunity, providing a promising and innovative therapeutic system for tumor treatment, and advancing the field of cancer immunotherapy.

Keywords: Engineered drug delivery system; Hydrogel microspheres; Immune checkpoint blocker; Innate and adaptive immune responses; Nanovesicles.

MeSH terms

Adaptive Immunity* / drug effects
Animals
Cell Line, Tumor
Humans
Immunity, Innate* / drug effects
Immunotherapy / methods
Macrophages
Mice
Microspheres*
Osteosarcoma* / immunology
Osteosarcoma* / pathology
Osteosarcoma* / therapy
Tumor Microenvironment / drug effects
Tumor Microenvironment / immunology