Synergistic Photodynamic–Chemotherapeutic Nanoplatform Induces Apoptosis to Counteract Drug-Resistant Breast Cancer

Standard chemotherapeutic regimens fail to provide adequate clinical outcomes in breast cancer owing to pervasive multidrug resistance. Here, we engineered dual-sensitization anti-resistant nanoparticles to manage recalcitrant breast cancer, seeking to capitalize on the combined benefits of photodynamic therapy and chemotherapy. A hyaluronic acid (HA) derivative and a chlorin e6 (Ce6) photosensitizer derivative were manufactured and validated by mass spectrometry. These compounds and the chemotherapeutic agent paclitaxel were co-formulated into nanoparticles using an emulsion-solvent evaporation procedure. The nanoparticles were evaluated with dynamic laser scattering, atomic force microscopy, and high-performance liquid chromatography (HPLC). Functional performance and mechanisms of action, both in vitro and in vivo, were assessed via flow cytometry, confocal/fluorescence microscopy, and a high-content screening platform. The designed dual-sensitization anti-resistant nanoparticles were spherical, measuring approximately 100 nm in diameter, and exhibited high paclitaxel encapsulation efficiency. They displayed potent suppression of drug-resistant breast cancer cell lines by boosting intracellular accumulation, generating synergistic anticancer activity between photodynamic therapy and chemotherapy, and triggering cell death through diverse signaling cascades. Acceptable in vivo efficacy, biocompatibility, and safety profiles were corroborated in murine tumor models. These dual-sensitization anti-resistant nanoparticles represent a viable strategy for addressing refractory breast cancer with precisely targeted treatment and limited systemic toxicity.