M1 Macrophage‐Derived Small Extracellular Vesicles as Synergistic Nanotherapeutics: Harnessing Intrinsic Anticancer Activity and Drug Delivery Capacity

ABSTRACT Small extracellular vesicles (sEVs) have emerged as next‐generation multifunctional nanotherapeutics due to their parental‐cell traits and role in intercellular communication. Among them, immune cell–derived sEVs are uniquely positioned to couple innate immunomodulatory activities with therapeutic payload delivery, making them highly attractive for cancer therapy. In particular, M1 macrophage‐derived sEVs (M1‐sEVs) preserve the tumour‐suppressive functions of their parent cells, including tumour microenvironment (TME) reprogramming, immune activation, and inhibition of cancer progression. However, the mechanisms by which these activities are coordinated within the TME, and whether they act independently or synergistically, remain poorly understood. Clarifying these mechanisms is crucial for harnessing their intrinsic bioactivity in combination with their natural capacity as drug delivery nanocarriers to optimize therapeutic efficacy. Here, we demonstrate that M1‐sEVs exhibit intrinsic stability and circulation longevity via ‘do not eat me’ ligands, as well as tumour‐homing ability revealed by proteomic profiling, enabling efficient uptake and deep infiltration in breast cancer models. Functionally, M1‐sEVs deliver antiproliferative microRNAs that suppress tumour metabolism, growth, and progression by inhibiting self‐renewal, adhesion, migration, motility, and invasion. Importantly, by integrating this endogenous bioactivity with exogenous doxorubicin loading, we achieved synergistic efficacy: a 3‐fold reduction in IC 50 in vitro (0.46 µM vs. 1.45 µM for free drug) and 70.18% tumour growth inhibition in vivo. These findings highlight M1‐sEVs as dual‐action nanotherapeutics that combine innate immune‐regulatory and tumour‐inhibitory functions with efficient drug delivery, advancing their development as powerful platforms for cancer therapy.