Calcite nanoparticles as advanced, pH-responsive platforms for cancer therapy: a comprehensive and critical review

Nanomedicine offers powerful opportunities to overcome the pharmacokinetic and microenvironmental limitations of conventional chemotherapy, particularly in aggressive breast cancer subtypes. Among emerging nanocarriers, calcium carbonate (CaCO₃) nanoparticles (NPs), have gained prominence owing to their excellent biocompatibility, full biodegradability into endogenous ions, low-cost fabrication, and intrinsic pH-responsiveness to the weakly acidic tumor microenvironment. Stable at physiological pH yet dissolving under tumor and endo/lysosomal acidity, these platforms enable site-specific release of chemotherapeutics, nucleic acids and photosensitizers (PSs) while buffering extracellular acidosis that drives chemoresistance and immune evasion. This review synthesizes advances in CaCO₃NP design, covering precipitation-, carbonation-, gas-diffusion-, emulsion- and polymer-mediated routes, and links process parameters to polymorph control, morphology, surface functionalization and drug-loading behavior relevant for tumor targeting. We critically discuss preclinical applications in monotherapy and multimodal regimens, including chemo-photodynamic and gene-immunotherapy strategies, with emphasis on breast cancer models where enhanced permeability and retention and active targeting are exploited to improve intratumoral accumulation and therapeutic index. In addition, we highlight theranostic CaCO₃constructs that integrate imaging capabilities for real-time tracking of biodistribution and treatment response, and outline translational challenges in scale-up, stability, safety and regulation. Finally, we discuss how artificial intelligence-guided formulation and design frameworks could accelerate clinical translation of calcite-based nanomedicines for precision oncology.