The Influence of the External Chemistry of Silica-Based Mesoporous Nanocarriers on Organ Tropism and the Inhibition of Pulmonary Metastases

<b>Background:</b> Mesoporous silica nanoparticles (MS NPs) have attracted significant interest for their role in the advancement of drug delivery systems. However, further investigation is needed to unravel the mechanisms behind the shift in organ tropism that occurs with changes in composition. <b>Methods:</b> To shed light on the correlation between their composition and organ-targeting capabilities, a range of MS NPs was synthesized and subsequently administered intravenously to mice. <b>Results:</b> Our results indicate that MS NPs with a pristine -Si-O-Si- framework, or those incorporating -C-C- or -S-S-S-S- bonds, predominantly accumulated in the liver. The shift to lung tropism was observed exclusively in MS NPs that were enriched with -SH groups. Proteomic analysis identified histidine-rich glycoprotein (HRG) as the most prevalent protein associated with liver-preferred MS NPs in serum, while lung-preferred MS NPs, such as thioether-bridged deformable hollow mesoporous organosilica nanoparticles (HSMONs), showed the highest affinity for albumin. Furthermore, the lung-selective HSMONs, endowed with inherent deformability and glutathione-responsive biodegradability, were utilized as systemic nanocarriers for the delivery of gambogic acid (GA). <b>Conclusions:</b> Leveraging albumin absorbing-triggered tumor cell targeting and trafficking, HSMONs conjugated with GA effectively elicited potent antitumor effects in pulmonary tissue.