Paeoniflorin-Copper-Coordinated Nanoparticles Targeting Dual Organelles Induce Lung Cancer Apoptosis

The intrinsic resistance of tumor cells to apoptosis frequently results in chemoresistance and therapeutic failure in clinical settings. The main active ingredients of traditional Chinese medicine, in combination with chemotherapy drugs, have become one of the effective treatment methods to overcome this kind of drug resistance by targeting double subcellular organelles to promote apoptosis. In this study, we developed a Cu²⁺-coordinated paeoniflorin (PF)/doxorubicin (DOX) biocomplex, referred to as PCD, with the aim of overcoming cellular apoptosis resistance for combinational lung cancer therapy. PCD demonstrates remarkable water solubility and superior in vivo biocompatibility. Owing to the coordination effect, the self-assembled PCD exhibits a nanoscale particle size, a narrow and homogeneous grain distribution, as well as exceptional dispersion stability. Furthermore, PCD has the potential to disassemble under conditions of high glutathione levels and low pH, thereby facilitating effective drug release. PF-mediated endoplasmic reticulum stress (ERS) can downregulate the expression of FDX1 and DLAT proteins. Ca²⁺ overload induced by ERS disrupts mitochondrial matrix ion balance, accelerates water efflux, and ultimately leads to mitochondrial volume reduction and a decrease in mitochondrial membrane potential. Ultimately, this process synergizes with DOX-induced reactive oxygen species production to enhance apoptosis in lung cancer cells. PCD exhibits significant superiority over monotherapy in inhibiting tumor growth while minimizing systemic toxicity via enhanced induction of lung cancer apoptosis. This study may provide a promising avenue for advancing self-delivery nanomedicine to overcome apoptosis resistance in lung cancer therapy.