Small intracellular vesicle-liposome fusogenic nanoplatform sIVs-LPs@Hes: Nebulized delivery targeting pulmonary inflammatory microenvironment to improve ALI

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are severe respiratory diseases with a high mortality rate, characterized by pathological lung damage induced by excessive inflammation. Current therapeutic strategies for ALI are limited; conventional treatments are associated with severe side effects and lack targeted efficacy. Hesperetin(Hes)is a natural flavanone abundant in citrus fruits that exhibits promising anti-inflammatory potential, yet its further clinical application is hindered by poor solubility and low bioavailability. Small intracellular vesicles (sIVs) derived from mesenchymal stem cells have been demonstrated to possess the advantages of high yield, rapid cellular uptake and excellent stability. In view of this, the present study constructed a Hes-loaded sIVs-liposome nanodelivery system (sIVs-LPs@Hes) for the treatment of ALI via nebulized inhalation. Our findings revealed that sIVs-LPs@Hes could be efficiently absorbed and persistently retained in the lung, and it exerted a superior protective effect by inhibiting glycolysis through the MCU-mCa²⁺-NF-κB pathway, promoting M2 polarization of macrophages, ameliorating pulmonary inflammatory status, reducing pulmonary edema and repairing pathological lung damage. In conclusion, the present study not only elucidated the specific anti-inflammatory mechanism of Hes, but also developed a novel composite nanodelivery system by integrating the merits of sIVs and liposomes, thereby providing a promising potential therapeutic strategy for ALI.