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Among them, immune cell\u2013derived sEVs are uniquely positioned to couple innate immunomodulatory activities with therapeutic payload delivery, making them highly attractive for cancer therapy. In particular, M1 macrophage\u2010derived sEVs (M1\u2010sEVs) preserve the tumour\u2010suppressive 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\u2010sEVs exhibit intrinsic stability and circulation longevity via \u2018do not eat me\u2019 ligands, as well as tumour\u2010homing ability revealed by proteomic profiling, enabling efficient uptake and deep infiltration in breast cancer models. Functionally, M1\u2010sEVs deliver antiproliferative microRNAs that suppress tumour metabolism, growth, and progression by inhibiting self\u2010renewal, adhesion, migration, motility, and invasion. Importantly, by integrating this endogenous bioactivity with exogenous doxorubicin loading, we achieved synergistic efficacy: a 3\u2010fold reduction in IC\n                    <jats:sub>50<\/jats:sub>\n                    in vitro (0.46 \u00b5M vs. 1.45 \u00b5M for free drug) and 70.18% tumour growth inhibition in vivo. These findings highlight M1\u2010sEVs as dual\u2010action nanotherapeutics that combine innate immune\u2010regulatory and tumour\u2010inhibitory functions with efficient drug delivery, advancing their development as powerful platforms for cancer therapy.\n                  <\/jats:p>","DOI":"10.1002\/jev2.70242","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T15:16:45Z","timestamp":1771514205000},"source":"Crossref","is-referenced-by-count":5,"title":["M1 Macrophage\u2010Derived Small Extracellular Vesicles as Synergistic Nanotherapeutics: Harnessing Intrinsic Anticancer Activity and Drug Delivery Capacity"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1502-1847","authenticated-orcid":false,"given":"Gaeun","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering University of Notre Dame  Notre Dame Indiana USA"},{"name":"Harper Cancer Research Institute 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