Dual-Responsive Peptide Nanoplatform for Improved Lung Cancer Therapy via the Synergistic Suppression of Autophagy and Drug Efflux

The efficacy of traditional chemotherapy in the treatment of non-small cell lung cancer (NSCLC) is often compromised by poor targeting, barriers posed by the tumor microenvironment, and active drug efflux. Furthermore, tumor cells significantly reduce their sensitivity to chemotherapeutic drugs by activating protective autophagy pathways, which is a key mechanism contributing to treatment failure. We designed and synthesized a smart responsive amphiphilic peptide, Pep1, featuring targeted modification with the Arg-Gly-Asp (RGD) peptide and triphenylphosphonium (TPP). Pep1 efficiently coloads paclitaxel (PTX) and hydroxychloroquine (HCQ) (PH/Pep1) and self-assembles into spherical nanoparticles. In vitro and in vivo experiments confirmed that PH/Pep1 not only efficiently entered lung cancer cells through active targeting to impair mitochondrial function but also inhibited autophagy, thereby preventing the clearance of damaged mitochondria. Through a synergistic “damaging mitochondria and inhibiting autophagy” cyclic mechanism, PH/Pep1 ultimately efficiently induced tumor cell apoptosis. Moreover, PH/Pep1 underwent a morphological transformation from nanospheres to nanofibers upon sequential stimulation by alkaline phosphatase (ALP) and reduced glutathione (GSH), which significantly increased drug retention and accumulation within tumor tissues. In a Lewis lung carcinoma (LLC) cell tumor-bearing mouse model, PH/Pep1 demonstrated the strongest tumor growth inhibition effect and good biosafety. In summary, the “dual-targeted/dual-responsive” synergistic therapeutic strategy proposed in this study provides a novel approach for designing highly efficient and precise nanodelivery platforms.