Magnetically-guided hyaluronic acid-decorated PLGA nanoparticles for enhanced tumor selective doxorubicin delivery in triple-negative breast cancer

Doxorubicin (Dox) is a potent chemotherapeutic agent for treating triple- negative breast cancer (TNBC), but its clinical utility is severely limited by non-specific biodistribution and dose-limiting systemic toxicity, particularly cardiotoxicity and nephrotoxicity. To address this clinical challenge, we developed hyaluronic acid (HA)-decorated PLGA nanoparticles co-loaded with superparamagnetic iron oxide (SPIO) and doxorubicin (HDSPs) and evaluated the potential of pulsed electromagnetic field (PEMF) guidance to enhance tumor-selective delivery. The platform integrates three targeting mechanisms: passive accumulation via optimal nanoparticle size and charge, HA-mediated engagement of the CD44 receptor, and PEMF-assisted magnetic guidance via SPIO. In CD44-positive MDA-MB-231 TNBC cells, HDSPs showed enhanced cellular internalization and intracellular doxorubicin delivery, and competitive blockade of CD44 with free HA reduced HDSP uptake, indicating a receptor-mediated component of internalization. PEMF exposure further increased intracellular iron uptake, whereas the accompanying differences in cell viability did not reach statistical significance. In TNBC xenograft models, localized PEMF application increased tumor accumulation of HDSPs by approximately 1.5-fold compared to non-PEMF treatment, with correspondingly lower signals in kidney and liver. The HDSP + PEMF system produced the greatest suppression of tumor growth among the groups tested, and no overt histopathological alterations were observed in heart or kidney at the dose and schedule used, in contrast to the changes seen after free doxorubicin. These findings suggest that combining HA-mediated CD44 engagement with PEMF-assisted magnetic guidance can improve tumor-selective doxorubicin delivery while limiting off-target exposure in TNBC, and support further evaluation of this strategy.