Hierarchical polymer-drug nanoplatform with polydopamine shell and folate targeting for synergistic cancer therapy

The clinical performance of paclitaxel (PTX) remains limited by poor tumor selectivity, systemic toxicity, and rapid clearance. In this study, we report the development of multifunctional polymeric nanoemulsions based on poly(ethylene brassylate-co-squaric acid) (PEBSA_Brij) designed for targeted and controlled anticancer delivery. The copolymer matrix integrates hydrophobic domains for PTX encapsulation and polar squaric acid moieties to enhance intermolecular interactions and structural tunability. Surface functionalization with polydopamine (PDA) enabled subsequent folic acid (FA) conjugation, aiming to promote receptor-mediated uptake in folate receptor-overexpressing breast cancer cells. Nanoemulsions with controlled size (170-181 nm), low polydispersity, and good colloidal stability were successfully obtained. Spectroscopic analyses confirmed polymer-drug interactions and surface modification. Antioxidant evaluation demonstrated radical scavenging capacity associated with the PDA layer, while loading of PTX enabled therapeutic potential. Biological evaluation on MCF-7 cells revealed enhanced cytotoxicity for FA-functionalized PTX-loaded nanoemulsions compared to non-targeted formulations, suggesting improved cellular internalization. At 24 h, PEBSA₁/PDA/FA/PTX (25/75) demonstrated the most rapid onset of cytotoxicity, with cell viability decreasing to approximately 90% at 5 mg/mL. The developed platform combines structural versatility, targeting capability, and dual-drug loading potential, highlighting PEBSA-based nanoemulsions as promising candidates for advanced breast cancer nanotherapy.