The presence of protein corona on the surface of nanoparticles modulates their physiological interactions such as cellular association and targeting property.It has been shown that α-mangostin(αM)-loaded poly(ethyle...The presence of protein corona on the surface of nanoparticles modulates their physiological interactions such as cellular association and targeting property.It has been shown that α-mangostin(αM)-loaded poly(ethylene glycol)-poly(l-lactide)(PEG-PLA)nanoparticles(NP-αM)specifically increased low density lipoprotein receptor(LDLR)expression in microglia and improved clearance of amyloid beta(Aβ)after multiple administration.However,how do the nanoparticles cross the blood‒brain barrier and access microglia remain unknown.Here,we studied the brain delivery property of PEG-PLA nanoparticles under different conditions,finding that the nanoparticles exhibited higher brain transport efficiency and microglia uptake efficiency afterαM loading and multiple administration.To reveal the mechanism,we performed proteomic analysis to characterize the composition of protein corona formed under various conditions,finding that both drug loading and multiple dosing affect the composition of protein corona and subsequently influence the cellular uptake of nanoparticles in b.End3 and BV-2 cells.Complement proteins,immunoglobulins,RAB5A and CD36 were found to be enriched in the corona and associated with the process of nanoparticles uptake.Collectively,we bring a mechanistic understanding about the modulator role of protein corona on targeted drug delivery,and provide theoretical basis for engineering brain or microglia-specific targeted delivery system.展开更多
基金This work was supported by National Natural Science Foundation of China(No.81722043,92068111,81973272,81803089,81903582,82073836)National Science and Technology Major Project(2018ZX09734005,2017ZX09304016,China)grant from Shanghai Science and Technology Committee(19410710100,18YF1413400,China).
文摘The presence of protein corona on the surface of nanoparticles modulates their physiological interactions such as cellular association and targeting property.It has been shown that α-mangostin(αM)-loaded poly(ethylene glycol)-poly(l-lactide)(PEG-PLA)nanoparticles(NP-αM)specifically increased low density lipoprotein receptor(LDLR)expression in microglia and improved clearance of amyloid beta(Aβ)after multiple administration.However,how do the nanoparticles cross the blood‒brain barrier and access microglia remain unknown.Here,we studied the brain delivery property of PEG-PLA nanoparticles under different conditions,finding that the nanoparticles exhibited higher brain transport efficiency and microglia uptake efficiency afterαM loading and multiple administration.To reveal the mechanism,we performed proteomic analysis to characterize the composition of protein corona formed under various conditions,finding that both drug loading and multiple dosing affect the composition of protein corona and subsequently influence the cellular uptake of nanoparticles in b.End3 and BV-2 cells.Complement proteins,immunoglobulins,RAB5A and CD36 were found to be enriched in the corona and associated with the process of nanoparticles uptake.Collectively,we bring a mechanistic understanding about the modulator role of protein corona on targeted drug delivery,and provide theoretical basis for engineering brain or microglia-specific targeted delivery system.
