Microfluidic-Assisted Silk Nanoparticles Co-Loaded with Epirubicin and Copper Sulphide: A Synergistic Photothermal-Photodynamic Chemotherapy Against Breast Cancer.

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has emerged as a promising non-invasive cancer treatment, addressing issues like drug resistance and systemic toxicity common in conventional breast cancer therapies. Recent research has shown that copper sulphide (CuS) nanoparticles and polydopamine (PDA) exhibit exceptional photothermal conversion efficiency under 808 nm near-infrared (NIR) laser irradiation, making them valuable for cancer phototherapy. However, the effectiveness of PDT is limited in hypoxic tumour environments, which are common in many breast cancer types, due to its reliance on local oxygen levels. Moreover, single-modality approaches, including phototherapy, often prove insufficient for complete tumour elimination, despite their therapeutic strength. In this paper, a microfluidic-assisted approach was used to create multifunctional silk-based nanoparticles (SFNPs) encapsulating the chemotherapeutic drug Epirubicin (EPI), the PTT/PDT agent CuS, and the heat-activated, oxygen-independent alkyl radical generator AIPH for combined chemotherapy, PTT, and PDT, with a polydopamine (PDA) coating for enhanced photothermal effects and surface-bound folic acid (FA) for targeted delivery in breast cancer treatment. The synthesised CuS-EPI-AIPH@SF-PDA-FA nanoparticles achieved a controlled size of 378 nm, strong NIR absorption, and high photothermal conversion efficiency. Under 808 nm NIR irradiation, these nanoparticles selectively triggered the release of alkyl radicals and EPI, improving intracellular drug levels and effectively killing various breast cancer cell lines while demonstrating low toxicity to non-cancerous cells. We demonstrate that novel core-shell CuS-EPI-AIPH@SF-PDA-FA NPs have been successfully designed as a multifunctional nanoplatform integrating PTT, PDT, and chemotherapy for targeted, synergistic breast cancer treatment.