Photoresponsive and Shape-Switchable MoS₂–Peptide-Hybrid Nanosystems for Enacting Photochemo and siRNA-Mediated Gene Therapy in Glioma

Exfoliated 2D transition-metal dichalcogenide (TMDCs)-based nanomaterials have captured a huge biomedical territory owing to their supreme physicochemical properties. However, the tedious and harsh chemical exfoliation of bulk MoS₂ impacts its utility in the biological domain. The study introduces a facile and environmentally benign way of shape-tunable exfoliation of bulk MoS₂ materials in an aqueous dispersion using designed self-assembled, tetrapeptide (Fmoc-HCKF-OH)-based nanostructures, generating hybrid MoS₂-peptide nanosystems for both tumor-targeted [employing folic acid (FA) functionalization] and NIR-responsive delivery of anticancer siRNA/drug in glioma. Exfoliated MoS₂-peptide NSs here prove to be an excellent photothermal agent by inducing a temperature elevation upto ∼51 °C upon 808 nm NIR absorption. Enhanced siRNA/Dox loading onto the 2D flat morphology of MoS₂-peptide NSs resulted in ∼90% cancer cell death in C6 glioma cells under NIR exposure. The expression of the Galectin-1 oncogene was suppressed following the treatment. Thereafter, analysis in the C6 glioma syngeneic rat model demonstrated a significant reduction (>10 fold) in tumor volume with siRNA/Dox-loaded FA-MoS₂-peptide NSs + NIR as compared to the phosphate buffer saline-treated control group. Further, <i>in vivo</i> biodistribution studies confirmed the higher targetability of FA-conjugated hybrid NSs. Taken together, our findings promote the utility of TMDC-based nanomaterials in conjecture with a biocompatible peptide scaffold as a trimodal chemo, gene, and phototherapeutic agent.