Metal (Au)-Decorated Chitosan-l-Arginine Polymeric Vector for Codelivery of Gefitinib and miR125b for Lung Cancer Therapy

The progression of lung cancer is highly associated with the aberrant activation of epidermal growth factor receptor (EGFR) tyrosine kinase and the positive feedback loop between cancer cells and tumor-associated macrophages (TAMs). Hence, we use chitosan (CS) as a backbone and l-Arginine (l-Arg) as lateral chains to synthesize a biocompatible copolymer [(CS)-co-(l-Arg)]. With the electrostatic coupling between Au particles and [(CS)-co-(l-Arg)], the copolymer was further fabricated into [(CS)-co-(l-Arg)]-(AuNPs) nanoparticles with a nest-type perforated structure (CAAu NPs). Owing to the perforated structure and cationic property, CAAu NPs exhibit a high capacity for coloading of gefitinib (GFT) and miR125b, forming GFT-miR125b@CAAu nanomedicine. GFT-miR125b@CAAu shows a pulmonary-anchoring advantage, which is attributed to the mucoadhesion of the CS backbone. Meanwhile, l-Arg residues play a biomimetic role, which endows GFT-miR125b@CAAu with efficient internalization by cancer cells through Arg transporter-mediated endocytosis. Within the acidic tumor microenvironment, the electrostatic bonding of GFT-miR125b@CAAu cleaves, which facilitates pH-responsive release of GFT and miR125b. By combination of EGFR blocking and miR125b augmenting, GFT-miR125b@CAAu nanomedicine not only inhibits cancer cell survival but also deactivates protumoral TAMs, implementing a combination therapy against lung cancer.