Nanomaterial Design for Macrophage Reprogramming: Emerging Strategies and Mechanistic Insights for Inflammation and...

Macrophages play a paradoxical role in inflammation and tumor. They can protect the host during acute inflammation but act as the main driver for the chronic inflammation which is a common characteristic of several diseases including rheumatoid arthritis, atherosclerosis, type 2 diabetes, inflammatory bowel disease, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In the tumor microenvironment, macrophages switch their phenotype to the immunosuppressive M2 state that promotes tumor growth, angiogenesis, and metastasis. Emerging nanomaterial platforms are trying to offer transformative solutions by enabling the precise delivery of immunomodulatory drugs directly to disease-site macrophages. This review will provide comprehensive comparative analysis of these emerging nanomaterial designs strategies across two disease paradigms: inflammatory diseases and tumor. The discussion will focus on various strategies which include inhibiting chemokine axis (CCL2-CCR2 axis), selective elimination of macrophages through apoptosis, metabolic reprogramming, biomimetic and apoptotic cell-inspired nanoparticles leveraging natural macrophage clearance pathways to promote M2 polarization in inflammation, and the activation of tumor-associated macrophages via TLR and STING agonist. We highlight the role of nanoparticle surface chemistry, composition, and targeting ligands in achieving the two opposite therapeutic outcomes of these two diseases while maintaining some common design principles including EPR-mediated accumulation at the disease sites and biomimetic modifications. We also mentioned novel next-generation nanoparticle-based platforms that are currently in clinical trials for the treatment of tumor and inflammatory diseases. Finally, we discuss the barriers that limit the clinical translational potential of broad nanoparticles, with particular emphasis on nanoparticle-related immunotoxicity, macrophage heterogeneity, and manufacturing reproducibility of the nanoparticles.