Platelet-derived extracellular vesicles (pEVs) are abundant nanoscale bioeffectors released during platelet storage, yet their functional roles in transfusion-associated complications remain largely unexplored. The present study demonstrates that pEVs act as potent nanocarriers that aggravate transfusion-related acute lung injury (TRALI) through activation of the Cd36–Fyn signaling pathway in macrophages. Integrated single-cell RNA sequencing and mechanistic analyses demonstrated that pEVs administration selectively induced M1 macrophage polarization and amplified pulmonary inflammation. Cd36 was markedly upregulated in the Fn1⁺ macrophage subset, serving as the receptor that mediates pEV uptake and Fyn activation. Molecular and pharmacological inhibition of Cd36–Fyn signaling significantly attenuated pro-inflammatory cytokine expression, lung tissue damage, and mortality in vivo. These findings elucidate how nanoscale platelet vesicles reprogram macrophage responses and disrupt immune homeostasis, providing a mechanistic framework for understanding TRALI progression. Identification of the Cd36–Fyn axis as a molecular link between nanovesicle signaling and immune dysregulation highlights new therapeutic opportunities for transfusion safety and nanomedicine-based interventions.