Glutamine modified lipid nanoparticles loaded with GPX4 siRNA for cervical cancer targeting
Despite significant efforts to develop nanocarriers for siRNA delivery, clinical application in cancer therapy has been hindered by inadequate tumor-targeting specificity, with cervical cancer particularly affected by poor tumor-specific targeting. Our previous work identified aberrant glutamine metabolism and ASCT2 overexpression in cervical cancer, providing a rationale for designing glutamine-ASCT2 interaction-based delivery systems. Based on this, we developed a self-fabricated microfluidic device for the preparation of lipid nanoparticles (LNP) and constructed a glutamine-modified lipid nanoparticle (GLN-LNP) for targeted siRNA delivery to cervical cancer. GLN-LNP exhibited significantly enhanced cellular uptake in both 2D cell monolayers and 3D tumor spheroid models. The competitive inhibition of uptake by free glutamine and the significant inhibition by an ASCT2-specific inhibitor V-9302 further confirm the critical role of the glutamine-ASCT2 interaction in facilitating LNP transport. GLN-LNP significantly decreased GPX4 expression in vitro at both transcriptional and translational level. In vivo results illustrated GLN-LNP had enhanced tumor accumulation capability compared to PEG-LNP, which has no glutamine modification. Additionally, GLN-LPN induced obvious in vivo GPX4 knockdown. These findings demonstrate GLN-LNP as a promising preclinical delivery system for cervical cancer, highlighting their potential to advance the clinical development of siRNA-based therapeutic.
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Funding
Chongqing Natural Science Foundation Grant CSTB2022NSCQMSX0754Chongqing Municipal Education Commission Grant KJQN202500406Chongqing Municipal Education Commission Foundation FundingNational Natural Science Foundation of China Grant 82204311Chongqing Graduate Student Research Innovation Project Grant CYS25345