Microfluidic fabrication of lipid-coated PLGA nanoparticles co-delivering CuS and curcumin for combined chemo-photothermal therapy

Cervical cancer remains a major global health challenge, with chemotherapy serving as a primary treatment modality. However, its clinical efficacy is often compromised by systemic toxicity, poor drug solubility, and non-specific targeting. To address these limitations, we report the fabrication of lipid-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) co-delivering curcumin (Cur) and copper sulfide (CuS) for combined chemo-photothermal therapy using a microfluidic swirl mixer. The microfluidic platform enables controlled, reproducible preparation of the NPs with low polydispersity (PDI) and high co-encapsulation efficiency of both compounds. The primary innovation of this work lies in integrating a PLGA -lipid hybrid architecture with simultaneous encapsulation of a model anticancer drug Cur and an NIR-responsive photothermal agent, CuS into a single formulation. Optimization of the flow rate ratio (FRR) and total flow rate (TFR) enabled precise tuning of particle size and physicochemical properties. CuS/Cur@PLGA@Lipid NPs the sustained drug release from the PLGA core with the improved colloidal stability and cellular uptake provided by the lipid shell. In vitro evaluations demonstrated pH-sensitive release, with accelerated Cur liberation under acidic microenvironments relative to physiological conditions. Furthermore, the NPs exhibited pronounced cytotoxicity against cervical cancer cells (HeLa), which was significantly enhanced under NIR laser irradiation via CuS-driven photothermal ablation. Quantitative fluorescence and flow-cytometry analyses confirmed superior cellular uptake and intracellular retention compared to free Cur, while multicellular tumor spheroid models demonstrated enhanced three-dimensional antitumor efficacy. Overall, this study provides an in vitro proof-of-concept for the high-throughput potential for the production of lipid-coated PLGA NPs with dual chemo-photothermal therapeutic potential.