M2 macrophage-derived exosomes (M2-Exos) are nanoscale vesicles enriched with bioactive cargo inherited from their parent M2 macrophages. Although M2-Exos emerge as a promising therapeutic agent due to their dual capacity of immunomodulation and tissue repair, they face critical limitations in applications, including low targeting specificity, cargo-loading capacity, and stability. Therefore, strategies are needed to construct engineered M2-Exos for enhancing therapeutic efficacy. In this review, we will first provide an overview of M2-Exos, including the preparation processes, parent cell sources, characterization, and delivery system. Second, we will examine advanced engineering approaches applied to M2-Exos, focusing on the enhancement of M2-Exos in terms of targeting specificity, payload retention, and microenvironment-responsive release kinetics. Third, we will introduce current applications of the engineered M2-Exos in the inflammatory diseases and regenerative medicine. The roles and the underlying therapeutic mechanisms of engineered M2-Exos in controlling inflammation and tissue regeneration are also discussed. Finally, we will also highlight the challenges in translating M2-Exos from bench to bedside, alongside perspectives for overcoming these barriers. By bridging mechanistic insights with emerging bioengineering technologies, future breakthroughs will unlock the full potential of engineered M2-Exos across precision therapy and cell-free tissue engineering. STATEMENT OF SIGNIFICANCE: M2 macrophage derived exosomes (M2-Exos) provide cell-free alternatives in regenerative medicine and immune regulation by utilizing the ability of M2 macrophages to regulate immune responses and coordinate tissue repair, yet their clinical translation is hindered by inherent limitations. Addressing these challenges through bioengineering strategies is critical to amplify their therapeutic efficacy and broaden clinical applicability. Recent advances in surface modification, cargo encapsulation, and stimulus-responsive delivery systems have significantly improved M2-Exos' targeting specificity, payload capacity, and controllability, making them precision tools for inflammatory diseases and regenerative medicine. This review not only provides a comprehensive framework for engineering M2-Exos but also offers insights into their mechanisms in resolving inflammation and promoting tissue repair.
