Each　type　of　cancer　has　its　own　specific　metastatic　route　developed　by　disseminating　circulating　tumor　cells　(CTCs)　and　related　extracellular　vesicles　to　the　target　organ,　i.e.,　metastasis　organotropism.　Tumor-derived　small　extracellular　vesicles　(herein　exosomes,　EXO)　play　an　important　role　in　determining　cancer　organotropic　metastases　to　pre-metastasis　niches.　We　therefore　hypothesized　that　drug-loaded　EXO　may　mix　well　with　their　companion　small　extracellular　vesicles　to　specifically　target　the　aimed　metastatic　organ　via　organotropism.　Here,　we　demonstrate　that　the　circulating　breast-cancer-derived　EXO　loaded　with　doxorubicin　(EXO-DOX)　can　mingled　with　their　original　companion　EXO　and　inhibit　breast　cancer　metastasis　to　lungs.　The　CD47　on　the　EXO-DOX　prevented　EXO-DOX　from　immune　attack　and　prolonged　their　circulation　in　blood.　The　tissue　distribution　ratio　of　EXO-DOX　is　identical　to　the　ratio　of　their　companion　EXO　due　to　the　specific　affinity　of　EXO　to　integrins　in　targeted　tissues.　Quantitative　accumulation　of　EXO-DOX　in　the　mouse　lungs　is　proportional　to　the　organotropism　of　the　circulating　breast　cancer　cells　that　disseminate　from　subcutaneously-implanted　human　breast　cancer　cells　in　mice.　EXO-DOX　inhibited　angiogenesis　and　cancer　cell　proliferation,　resulting　in　prevention　of　breast　cancer　metastasis　to　the　lungs.　This　study　opens　a　novel　path　to　use　Trojan　small　extracellular　vesicles　for　specifically　controlled　release　of　active　components　by　small　extracellular　vesicles　organotropism　mechanism　to　the　targeted　organ　for　disease　chemoprevention.　©　2021　Elsevier　B.V.