Enhancing Magnetic Hyperthermia at the Cell Membrane by Anchoring 92R‐Functionalized Magnetic Nanoparticles to Low‐Endocytic CCR9 Surface Receptors

Magnetic hyperthermia therapy (MHT) is a promising cancer treatment that has demonstrated efficacy in phase I and II clinical trials for glioblastoma and prostate cancer. MHT relies on heat generated by magnetic nanoparticles (MNPs) when exposed to alternating magnetic fields (AMFs). The heat output depends not only on the intrinsic properties of MNPs but also on extrinsic factors such as the extracellular and intracellular environments. Aggregation of MNPs under certain conditions can significantly reduce therapeutic efficiency. To overcome this limitation, we present a strategy to enhance MHT by modulating MNP-cell interactions. We functionalized dimercaptosuccinic acid (DMSA)-coated MNPs with the 92R antibody (DMSA-MNPs@92R), which selectively binds to the low-internalization chemokine receptor CCR9, overexpressed in certain tumors. Exposure of CCR9⁺ MOLT-4 cells to DMSA-MNPs@92R under AMFs resulted in enhanced tumor cell death. Our approach enables spatially controlled binding, maintaining MNPs in a less-aggregated state and at an optimal distance from the cell membrane to maximize heat generation. Mechanistic analysis confirmed that cytotoxicity is driven by localized hyperthermia at the subcellular level rather than a macroscopic temperature increase. These findings underscore the potential of controlled MNPs-cell interactions to improve in vitro MHT performance and open an interesting avenue for enhancing therapeutic efficacy.