Engineering Macrophage via Biomaterial-Mediated Mitochondrial Regulation: Mechanisms and Strategies

Precisely targeting mitochondria to regulate macrophage fate has emerged as a critical therapeutic paradigm for managing inflammation-related pathologies. Mitochondria, while known for producing ATP, have been increasingly recognized for their critical involvement in immune cell differentiation and activation. As key innate immune effectors, macrophages dynamically adapt to microenvironmental cues through metabolic reprogramming and phenotype polarization, processes fundamentally controlled by mitochondrial homeostasis. Organelle-specific therapeutic advances now position mitochondria-targeted strategies as precision interventions with spatiotemporal advantages over conventional approaches. Crucially, these rationally designed systems demonstrate remarkable potential not only to direct macrophage differentiation toward anti-inflammatory phenotypes but also to reprogram the immune microenvironment concurrently, thereby achieving a breakthrough in precision medicine for inflammatory disorders. This review analyzes mitochondrial homeostasis mechanisms in pathophysiology, establishing design principles for targeted therapies. We classify emerging mitochondrial modulation approaches into indirect regulation and direct targeting, evaluating their impacts on macrophage plasticity and therapeutic efficacy. Critical translational challenges are examined, including single-cell-centric regulation, the complexity of mitochondrial interactions in macrophages, and the inefficiency of traditional trial-and-error strategies. The proposed artificial intelligence (AI)-driven methods such as deep learning-based material design, metabolic network modeling, and advanced small-molecule synthesis can accelerate the development of targeted mitochondrial therapies and enhance clinical feasibility. This synthesis aims to accelerate the development of mitochondrially engineered immunotherapies through rational design principles and standardized evaluation protocols.