As the prevalence of vascular calcification (VC), a strong contributor to cardiovascular morbidity and mortality, continues to increase, the need for pharmacologic therapies becomes urgent. Sodium thiosulfate (STS) is a clinically approved drug for therapy against VC; however, its efficacy is hampered by poor bioavailability and severe adverse effects. Plant-derived extracellular vesicles have provided options for VC treatment since they can be used as biomimetic drug carriers with higher biosafety and targeting abilities than artificial carriers. Inspired by natural grapefruit-derived extracellular vesicles (EVs), we fabricated a biomimetic nanocarrier comprising EVs loaded with STS and further modified with hydroxyapatite crystal binding peptide (ESTP) for VC-targeted delivery of STS. In vitro, the ESTP nanodrug exhibited excellent cellular uptake capacity by calcified vascular smooth muscle cells (VSMCs) and subsequently inhibited VSMCs calcification. In the VC mice model, the ESTP nanodrug showed preferentially the highest accumulation in the calcified arteries compared to other treatment groups. Mechanistically, the ESTP nanodrug significantly prevented VC via driving M2 macrophage polarization, reducing inflammation, and suppressing bone-vascular axis as demonstrated by inhibiting osteogenic phenotype trans-differentiation of VSMCs while enhancing bone quality. In addition, the ESTP nanodrug did not induce hemolysis or cause any damage to other organs. These results suggest that the ESTP nanodrug can prove to be a promising agent against VC without the concern of systemic toxicity.