Receptor Independent Magnetoelectric Nanocarriers for Spatiotemporally Controlled Chemotherapy of Triple Negative Breast Cancer Variants, Ovarian Cancer, and Prostate Cancer

In cancer therapeutics, the lack of selective and controllable drug delivery remains a major barrier to effective treatment of aggressive and metastatic tumors. Anthracycline chemotherapies such as doxorubicin (Dox) are widely used but are limited by systemic toxicities, especially cardiotoxicity. Nanomedicine approaches have attempted to overcome these challenges, yet many platforms still suffer from inconsistent targeting and inefficient intracellular drug release. Building on our previous demonstration of magnetoelectric silica nanoparticles (MagSiNs) as multimodal MRI contrast agents and on‑demand Dox-delivering nanocarriers in metastatic cancer cells, here we extend this platform to a broader, more mechanistically defined setting. MagSiNs consist of a magnetic cobalt ferrite (CoFe₂O₄) core and a piezoelectric silica shell that together enable magnetoelectric guidance and triggered drug release in a receptor‑independent manner. Across multiple cancer models, including triple‑negative breast cancer (MDA‑MB‑231, HCC70, HCC1500), ovarian (A2780), and prostate (PC3) cells, Dox‑loaded MagSiNs achieved efficient intracellular delivery and selective cytotoxicity while sparing normal endothelial cells (HUVEC). For example, 500 nM Dox‑MagSiNs reduced HCC1500 viability to 14% compared with 42% for 500 nM free Dox, while Dox-MagSiNs preserved high HUVEC viability relative to free Dox. Mechanistic studies revealed that MagSiNs are taken up predominantly through dynamin‑dependent, clathrin‑mediated endocytosis, accumulate in endo‑lysosomal compartments, and release their drug payload upon magnetoelectric activation. Together, these results advance MagSiNs from a proof‑of‑concept delivery system to a stable and tunable nano-platform that enables externally regulated, receptor‑independent chemotherapy across diverse cancer types. Future integration with magnetic resonance imaging could provide real‑time theragnostics capabilities, enabling simultaneous tumor visualization and magnetically triggered drug delivery.