Macrophages: Redefining extracellular matrix architecture through phenotypic switches as therapeutic targets

Bingyang Dai; Lizhen Zheng; James Chung-Wai Cheung; Yufeng Long; Jun Liu; Chunyi Wen; Ling Qin; Cheng Dong

doi:10.1016/j.biomaterials.2026.124063

Macrophages: Redefining extracellular matrix architecture through phenotypic switches as therapeutic targets

Biomaterials. 2026 Jul:330:124063. doi: 10.1016/j.biomaterials.2026.124063. Epub 2026 Feb 14.

Authors

Bingyang Dai¹, Lizhen Zheng², James Chung-Wai Cheung³, Yufeng Long⁴, Jun Liu⁵, Chunyi Wen⁵, Ling Qin⁶, Cheng Dong⁷

Affiliations

¹ Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China; The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China. Electronic address: bingydai@polyu.edu.hk.
² Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Hong Kong SAR, China; Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial & Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Areas of Excellence Centre for Musculoskeletal Degeneration and Regeneration, Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
³ Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China.
⁴ Department of Spine Surgery, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, China; Musculoskeletal Research Laboratory, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, China.
⁵ Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China; The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.
⁶ Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial & Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Areas of Excellence Centre for Musculoskeletal Degeneration and Regeneration, Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: lingqin@cuhk.edu.hk.
⁷ Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China; The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China. Electronic address: cheng.dong@polyu.edu.hk.

PMID: 41713050
DOI: 10.1016/j.biomaterials.2026.124063

Abstract

Macrophages, as central orchestrators of tissue homeostasis, exhibit remarkable developmental and functional plasticity across diverse physiological and pathological contexts. Mechanistically, microenvironmental cues govern phenotypic switching, while dysregulated crosstalk with stromal cells drives fibrosis and chronic inflammation. Emerging therapeutic strategies targeting macrophages demonstrate potential in restoring tissue homeostasis. However, challenges persist in achieving spatiotemporal precision and balancing pro-repair versus pro-fibrotic outcomes. This review synthesizes current understanding of macrophage biology, encompassing their developmental origins, phenotypic heterogeneity in tissue-specific niches, and multifaceted roles in extracellular matrix (ECM) remodeling, immune surveillance, and organ homeostasis. A comprehensive view of the macrophage regulatory landscape highlights that precise spatiotemporal regulation serves as the cornerstone for macrophages to restore tissue homeostasis. Multiple innovative strategies, including macrophage-based drug delivery systems, cellular and genetic engineering of macrophages, and synergistic macrophage treatment modalities, are expanding the technical frontiers for disease diagnosis and therapeutic intervention. Future directions emphasize integrating multi-omics profiling, synthetic biology, and AI-aided biomaterials to develop 'smart' therapeutics that dynamically steer macrophage functionality. Such synergy will unravel context-dependent signaling and subset-specific interactions, which further advances our understanding of macrophage biology and its translational potential in resolving refractory diseases, and bridges mechanistic insights into transformative clinical applications.

Keywords: Biomaterials-based immunotherapy; Drug delivery; Extracellular matrix (ECM); Fibrosis and inflammation; Macrophage; Tissue-resident macrophages.

Publication types

Review

MeSH terms

Animals
Drug Delivery Systems
Extracellular Matrix* / metabolism
Humans
Macrophages* / cytology
Macrophages* / immunology
Macrophages* / metabolism
Phenotype