Tumor-Targeting monodisperse hydroxyapatite core–shell nanospheres for overcoming multidrug resistance in cancer therapy via tumor-specific synergistic calcium overload

Multidrug resistance (MDR) remains a central obstacle in cancer therapy, accounting for over 90% of cancer-related mortality. Although calcium overload has emerged as a promising anticancer strategy, its clinical translation is largely limited by insufficient tumor selectivity. Hydroxyapatite nanoparticles (HAPNs) possess intrinsic biocompatibility and the ability to induce tumor-specific Ca 2+ overload; however, conventional synthesis methods often yield polydisperse and aggregation-prone particles, resulting in high dosage requirements and inconsistent antitumor efficacy. Herein, we reported a tumor-targeting monodisperse hydroxyapatite core–shell nanospheres (TMHCNs) fabricated via microfluidic coaxial chips (MCC)-assisted soft-templating strategy to achieve precise physicochemical control for tumor-specific synergistic Ca 2+ overload therapy. FDA-approved components, sebacic acid, glycerol, and polyethylene glycol, were used to compose uniform nanomicelles as soft templates for homogeneous mineralization, enabling reproducible generation of uniform core–shell nanospheres. Subsequent surface functionalization with hyaluronic acid (HA) yielded monodisperse tumor-targeting nanospheres, TMHCNs (47.0 ± 5.0 nm) with enhanced CD44-mediated cellular uptake. The antimalarial drug and sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) inhibitor, artemisinin (Art), was then selected and encapsulated into TMHCNs to construct the synergistic Ca 2+ overload nanosystem Art@TMHCNs. TMHCNs alone induced sustained and tumor-selective intracellular Ca 2+ overload. Loading the SERCA inhibitor Art further amplified tumor-specific Ca 2+ overload, triggered mitochondrial dysfunction, depleted ATP, and activated both intrinsic and extrinsic apoptotic pathways, thereby effectively reversing MDR. In an A549/PTX xenograft model, Art@TMHCNs achieved complete tumor growth suppression and pronounced tumor-specific calcification with minimal off-target toxicity. This work establishes a precisely engineered, monodisperse hydroxyapatite core–shell platform that amplifies tumor-specific calcium dysregulation and provides a clinically translatable strategy for safe and effective MDR reversal in cancer therapy.