Zih-An ChenCheng-Hsun WuSi-Han WuChiung-Yin HuangCHUNG-YUAN MOUKuo-Chen WeiYun YenI-Ting ChienSabiha RunaYi-Ping ChenPeilin Chen2024-07-162024-07-162024-05-08https://scholars.lib.ntu.edu.tw/handle/123456789/719842Mesoporous silica nanoparticles (MSNs) represent a promising avenue for targeted brain tumor therapy. However, the blood–brain barrier (BBB) often presents a formidable obstacle to efficient drug delivery. This study introduces a ligand-free PEGylated MSN variant (RMSN25-PEG-TA) with a 25 nm size and a slight positive charge, which exhibits superior BBB penetration. Utilizing two-photon imaging, RMSN25-PEG-TA particles remained in circulation for over 24 h, indicating significant traversal beyond the cerebrovascular realm. Importantly, DOX@RMSN25-PEG-TA, our MSN loaded with doxorubicin (DOX), harnessed the enhanced permeability and retention (EPR) effect to achieve a 6-fold increase in brain accumulation compared to free DOX. In vivo evaluations confirmed the potent inhibition of orthotopic glioma growth by DOX@RMSN25-PEG-TA, extending survival rates in spontaneous brain tumor models by over 28% and offering an improved biosafety profile. Advanced LC-MS/MS investigations unveiled a distinctive protein corona surrounding RMSN25-PEG-TA, suggesting proteins such as apolipoprotein E and albumin could play pivotal roles in enabling its BBB penetration. Our results underscore the potential of ligand-free MSNs in treating brain tumors, which supports the development of future drug–nanoparticle design paradigms.enmesoporous silica nanoparticlesbrain tumorblood−brain barrierthe enhanced permeability and retention effectdoxorubicinprotein corona[SDGs]SDG3journal article10.1021/acsnano.3c08993