Chitosan-based nanotheranostics integrated dual-modal imaging and combinatorial tumor therapy for EGFR-TKI resistance reversal

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are primary treatments for EGFR-mutated non-small cell lung cancer (NSCLC), but acquired resistance limits efficacy. To address this challenge, we developed CsO/IGA, a multifunctional nanoplatform combining osimertinib (AZD9291) with an indocyanine green-gadolinium (ICG-Gd) probe via oleanolic acid (OA)-modified chitosan encapsulation, integrating fluorescence/magnetic resonance imaging (FLI/MRI) with chemo-phototherapy and tumor microenvironment (TME) modulation. CsO/IGA (∼100 nm) demonstrated excellent stability and generated both singlet oxygen and hyperthermia under 808 nm irradiation. The nanoplatform exerted efficient anti-cancer effects to overcome resistance through reactive oxygen species induction, mitochondrial membrane potential reduction, and EGFR/phosphorylated EGFR downregulation in sensitive and resistant NSCLC cells. Notably, the OA component suppressed cancer-associated fibroblasts and α-smooth muscle actin expression, remodeling the TME to enhance tumor penetration. In vivo studies confirmed tumor-specific accumulation and deep penetration, FLI/MRI capability, and superior antitumor efficacy through chemo-phototherapy synergy. This work presents a promising OA-integrated theranostic strategy integrating targeted therapy, phototherapy, TME modulation, and diagnostic imaging for overcoming EGFR-TKI resistance in NSCLC.