Nanoengineered Metformin Delivery System Targeting the AMPK/ PI3K/Akt/mTOR Pathway: A Potential Therapeutic Strategy...

Cisplatin, an effective antitumor drug, is clinically limited by its dose-dependent nephrotoxicity. Rational nanocarrier design offers a strategy to improve drug delivery and minimize off-target effects. In this work, we developed a metformin-loaded mesoporous silica nanoparticle (MSNP) system, which was further coated with chitosan (CTS) and tailored into distinct sizes and geometries (elliptical vs. rounded) to enhance bioactivity, kidney targeting, and biocompatibility.

Thirty-five rats were divided into seven groups after nephrotoxicity induction with cisplatin (2 mg/kg, intraperitoneally, once weekly for 4 weeks). Groups were treated orally with metformin, uncoated MET-MSNPs, or CTS-coated MET-MSNPs (elliptical and rounded; 40 mg/kg orally daily for 4 weeks. Biochemical markers, histology, and immunohistochemistry were performed to evaluate renal function and tissue remodeling.

Cisplatin exposure induced oxidative stress, elevated TGF-β1, TNF-α, IL-1β, and caspase- 3 levels, and caused renal dysfunction with marked histopathological damage. Both MET and CTS-MET-MSNPs mitigated these changes, with geometry- and coating-dependent improvements in renal biomarkers and tissue recovery. qPCR analysis showed that CTS-MET-MSNPs significantly downregulated cisplatin-induced AMPK/PI3K/Akt and restored mTOR expression. CTS-coated carriers showed superior anti-inflammatory, antioxidant, and anti-apoptotic effects compared with free MET.

In light of the available evidence, the design of our carrier system was guided by key parameters known to enhance kidney targeting. Rounded nanoparticles were selected since their geometry has been reported to promote efficient circulation, facilitate passage through the glomerular filtration barrier, and improve interaction with renal tissues. In addition, surface functionalization with chitosan was introduced to confer a positive charge, which is expected to favor electrostatic interactions with the negatively charged renal cell membranes. Accordingly, for our formulation strategy, rounded particles with a CH coating were deliberately chosen to maximize kidney selectivity. The morphological assessment of CTS-MET-MSNPs by TEM showed the successful formulation of the rounded nanoparticles with a defined mesoporous structure.

This study demonstrated that the CTS-MET-MSNPs offer a superior strategy for mitigating cisplatin-induced acute kidney injury compared to free metformin. By optimizing the vehicle's architecture using rounded geometry to promote favorable glomerular filtration kinetics and applying a positively charged chitosan coating to exploit electrostatic binding with negatively charged renal membranes. We achieved highly site-specific kidney targeting. Morphological evaluation via TEM confirmed the successful fabrication of these rounded nanoparticles with a well- defined mesoporous framework. Biologically, the CTS-MET-MSNPs suppressed cisplatin-mediated oxidative stress, cellular damage, and histopathological degradation, outperforming free MET. Most notably, qPCR analysis revealed that this advanced nanoformulation achieved its potential anti- inflammatory, antioxidant, and anti-apoptotic properties by precisely downregulating the cisplatin- induced AMPK/PI3K/Akt pathway and restoring downstream mTOR expression. Collectively, these findings highlight CTS-MET-MSNPs as a highly potent, targeted nanomedicine capable of maximizing the clinical protective window of metformin against chemotherapeutic nephrotoxicity.