Macrophages, as pivotal constituents of the immune system, play central roles in orchestrating inflammatory responses and bridging innate and adaptive immunity. Beyond their defensive functions, these versatile immune cells serve as critical regulators in maintaining tissue homeostasis and coordinating repair processes [1,2]. When exposed to trauma or bacterial infection, macrophages exhibit remarkable functional plasticity and adaptability. Their diverse biological responses, ranging from destructive pro-inflammatory actions to protective regenerative activities, are governed by precise regulatory mechanisms involving cellular activity balance and metabolic reprogramming, which collectively influence inflammatory progression and tissue recovery [3]. The regulation of the inflammatory microenvironment is intrinsically linked to regenerative outcomes. A balanced inflammatory response is a prerequisite for effective tissue repair, while uncontrolled inflammation hinders tissue regeneration.

Macrophages possess multi-directional polarization and exhibit high heterogeneity. The dynamic polarization of macrophages is mediated through complex signaling pathways and microenvironmental cues. Traditionally, macrophages are classified into pro-inflammatory M1 phenotypes or alternatively activated into anti-inflammatory M2 phenotypes. M1 macrophages, activated by stimuli such as lipopolysaccharide (LPS) and interferon-gamma (IFN-γ), drive inflammatory cascades through secretion of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and IL-6. These mediators not only amplify innate immune responses but also potentiate adaptive immunity by enhancing antigen presentation and T-cell activation. In contrast, M2 macrophages, alternatively activated by IL-4 and IL-13, secrete anti-inflammatory mediators such as IL-10 to resolve excessive inflammation and initiate tissue remodeling programs. Recent researches have significantly advanced the understanding of macrophage phenotypes, the identification of the M1, M2, M3, M4, M17, Mreg, Mmox, Mhem, M (Hb) and HA-Mac phenotypes has yielded new insights into the complexity of macrophage biology and its role in various diseases [4]. For instance, M3 macrophages represent a hybrid phenotype co-expressing M1 markers and partial M2 traits, thereby exhibiting dual pro-inflammatory and anti-tumor activities. Meanwhile, regulatory macrophages (Mreg) represent an anti-inflammatory phenotype and possess the capacity to suppress immune responses.

Among these subtypes, M2 macrophages remain the most studied and therapeutically promising subtype due to their potent anti-inflammatory and pro-regenerative properties [5,6]. Emerging evidence demonstrates that the differentiation into M2 phenotypes or M2-like states is indispensable in tissue regeneration. These M2 macrophages ameliorate the local immune microenvironment, suppressing pro-inflammatory signaling, promoting angiogenesis, and facilitating extracellular matrix deposition, thereby mitigating the detrimental effects of uncontrolled inflammation [[7], [8], [9], [10]]. The immune-modulatory and anti-inflammatory capabilities of M2 macrophages are governed by intrinsic signaling pathways. Efforts have been made in leveraging the therapeutic potential of M2 macrophages. Ongoing researches are focused on modulating macrophage populations, regulating their phenotypic transitions, and orchestrating molecular regulatory mechanisms to alleviate or treat a wide range of diseases [2].

Despite their considerable therapeutic potential, the direct use of M2 macrophages is hinder by significant challenges related to cell expansion and transplantation [11]. One major hurdle is the time-consuming cell culture process. For instance, M2 macrophages often require 48-72 hours of in vitro IL-4/IL-13-induced polarization protocols to achieve the desired functional state [12]. Additionally, cell viability assays must be performed frequently during the culture process. Other challenges include phenotype instability, where macrophages may lost their phenotype during prolonged culture, and the low post-transplantation survival rate, as M2 macrophages are usually undetectable four weeks after transfer [13,14]. In recent years, exosomes (Exos), nanoscale extracellular vesicles derived from cells, has emerging as a promising cell-free therapeutic alternative [15]. These extracellular vesicles, released by a wide range of cell types, effectively replicate the biological properties and functions of their parent cells [16,17]. Hence, macrophage-derived exosomes (M-Exos) have attracted growing interest due to their role as critical mediators of intercellular communication. M-Exos are capable of transferring diverse biological information and macromolecules from macrophages to recipient cells, thereby modulating a variety of physiological and pathological processes [18,19]. These nanoscale vesicles, inheriting the beneficial properties of macrophages, including innate inflammatory targeting, immunomodulatory capabilities, and regenerative properties. Moreover, they provide a stable and scalable platform for molecular engineering to enhance their regenerative potential. M-Exos are categorized into unpolarized M0 macrophage-derived Exos (M0-Exos), polarized M1 and M2 macrophage-derived Exos (M1-Exos and M2-Exos, respectively) [[20], [21], [22]]. Notably, M2-Exos not only exhibit the ability to reprogram pro-inflammatory M1 macrophages, but also carry various bioactive molecules that play pivotal roles in promoting cell proliferation, differentiation, and tissue homeostasis [23,24]. These properties make M2-Exos more effective than M1 or M0 exosomes in promoting bone regeneration, angiogenesis, neuroprotection, and wound healing [25,26].

Although the natural features of M2-Exos offer certain therapeutic benefits, they are not fully optimized for clinical applications. Native M2-Exos face several limitations, including insufficient targeting specificity, limited cargo-loading capacity, and low stability and systemic circulation [18]. These challenges highlight the need for engineering strategies to enhance their regenerative potential and therapeutic outcomes. Through engineering, M2-Exos can be tailored to exhibit desirable properties to overcome above-mentioned limitations, serving as a molecular bridge between inflammation regulation and regenerative medicine. The purpose of this review is to offer a thorough summary of the advancements in M2-Exos engineering, offering inspiration and reference for future researchers to tailor these exosomes according to specific needs, thereby expanding their therapeutic applications. Therefore, this review aims to provide a comprehensive summarize of the latest advancements in M2-Exos engineering. By analyzing the current state of research, we will introduce the principal methodologies and applications of engineered M2-Exos in the fields of inflammation regulation and tissue engineering. We will also discuss the remaining challenges and explore the future directions that could propel the development of engineered M2-Exos. This review seeks to inspire researchers to refine M2-Exos-based therapeutic strategies with enhanced precision to meet specific therapeutic requirements, bridging the gap between foundational research and clinical translation.