Manipulating calcium homeostasis with nanoplatforms for enhanced cancer therapy

Abstract

Calcium ions (Ca²⁺) are indispensable and versatile metal ions that play a pivotal role in regulating cell metabolism, encompassing cell survival, proliferation, migration, and gene expression. Aberrant Ca²⁺ levels are frequently linked to cell dysfunction and a variety of pathological conditions. Therefore, it is essential to maintain Ca²⁺ homeostasis to coordinate body function. Disrupting the balance of Ca²⁺ levels has emerged as a potential therapeutic strategy for various diseases, and there has been extensive research on integrating this approach into nanoplatforms. In this review, the current nanoplatforms that regulate Ca²⁺ homeostasis for cancer therapy are first discussed, including both direct and indirect approaches to manage Ca²⁺ overload or inhibit Ca²⁺ signalling. Then, the applications of these nanoplatforms in targeting different cells to regulate their Ca²⁺ homeostasis for achieving therapeutic effects in cancer treatment are systematically introduced, including tumour cells and immune cells. Finally, perspectives on the further development of nanoplatforms for regulating Ca²⁺ homeostasis, identifying scientific limitations and future directions for exploitation are offered.

Keywords: Ca2+ inhibition; Ca2+ overload; calcium homeostasis regulation; cancer therapy; immunotherapy.

FIGURE 1

Schematic illustration of different strategies for regulating Ca²⁺ balance in cancer treatment (Ca²⁺ overload/inhibition), and the applications of Ca²⁺‐related nanomaterials in different cells (cancer cells, immune cells) to regulate their Ca²⁺ balance for achieving therapeutic effects in cancer treatment.

FIGURE 2

CaCo₃ as intelligent carrier to deliver different types of cargos. (A) Scheme illustration of the biomineralization processes of DNA@CaCO₃ with cGAS‐STING activating abilities to inhibit tumour recurrence. (B) TEM image of DNA@CaCO₃ microparticles. (C) pH‐responsive decomposition properties of DNA@CaCO₃ microparticles and (D) time‐dependent release curves of DNA from DNA@CaCO₃ microparticles. (E) Western blotting of the proteins correlated with cGAS‐STING‐TBK1‐IRF3 signalling pathways. (F) Tumour growth curves of B16 tumours in C57BL/6 mice and (G) CT26 tumours in BALB/c mice. Reproduced with permission.^{[ 39 ]} Copyright 2023, American Chemical Society.

FIGURE 3

CaCO₃ based nanoplatform for Ca²⁺ overload. (A) Scheme of CaCO₃@PDA@CUR@CDDP‐based synergistic Ca²⁺ overload and chemotherapy. (B) Mitochondrial Ca²⁺ concentrations quantification after treated with various Ca²⁺ nanomodulators. (C) Tumour growth curves of MCF‐7‐tumour‐bearing nude mice. Reproduced with permission.^{[ 45 ]} Copyright 2021, John Wiley & Sons. (D) Schematic diagram of the synthesis process of CaCO₃@COF‐BODIPY‐2I@GAG NMs. (E) Molecular structure of DMTP, TPB, BODIPY‐2I, GAG, AND TPB‐DMTP‐COF (1). (F) Synergistic induction of intracellular Ca²⁺ overload by singlet oxygen (¹O₂) and exogenous Ca²⁺ delivery. Note: (A) CD44‐mediated cellular uptake; (B) CaCO₃ decomposition in lysosomes; (C) BODIPY‐2I induce ¹O₂ production under green LED. (D) Mitochondrial impairment. (E) Cell blebbing induced by oncosis. Reproduced with permission.^{[ 46 ]} Copyright 2020, John Wiley & Sons.

FIGURE 4

CaO₂‐based nanoplatform for Ca²⁺ overload and CDT. (A) Schematic illustration of the synthesis process of CaO₂‐CuO₂@HA NC and (B) antitumour properties of CaO₂‐CuO₂@HA NC for Ca²⁺ overload and CDT. Reproduced with permission.^{[ 54 ]} Copyright 2022, American Chemical Society. (C) Schematic illustration of the synthesis process of CaZFCP and (D) therapeutic mechanism of pH‐responsive CaZFCP for Ca²⁺ overload, CDT and PDT. (E) Hypoxia‐inducible factor‐1α (HIF‐1α) staining of tumour tissues after treated with PBS, ZFCP, and CaZFCP. Reproduced with permission.^{[ 55 ]} Copyright 2021, John Wiley & Sons.

FIGURE 5

CaH₂‐based nanoplatform for Ca²⁺ overload, H₂ therapy and acidic TME modulation. (A) Schematic illustration of the application of nano‐CaH₂ for mouse xenograft and interventional transarterial embolization (TAE) therapy of rabbit liver tumours through the combination of Ca²⁺ overload, H₂ immunotherapy and neutralization of acidic tumour microenvironment. (B) Mitochondrial dysfunction and ATP generation inhibition. (C) Intracellular Ca²⁺ content after different treatment. (D) characterization of ICD. (E) Tumour volume monitoring. (F) pH values inside the tumours. (G) CTL infiltration, (H) quantification of Treg cells, and (I) the polarization of macrophages within the primary and distant tumours after different treatments. Reproduced with permission.^{[ 60 ]} Copyright 2022, Elsevier.

FIGURE 6

CaP‐based nanoplatform for Ca²⁺ overload. (A) Schematic illustration of dual enhanced Ca²⁺ nanogenerator (DECaNG) synergized with Ca²⁺ overload and PTT. DECaNG induces tumour cell apoptosis both (B) in vitro and (C) in vivo. Reproduced with permission.^{[ 70 ]} Copyright 2018, American Chemical Society. (D) Schematic illustration of the anti‐tumour mechanism of RGD‐CaPO/DOX in tumour cells and peritoneal cavity of mice. (E) Western blotting of the proteins correlated with endoplasmic reticulum stress. (F) Fluorescent images to detection the intracellular Ca²⁺. (G) Survival proportions of mice after different treatments. (H) Hematoxylin−eosin (H&E) and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) images of tumour tissues after different treatments. Reproduced with permission.^{[ 67 ]} Copyright 2022, American Chemical Society.

FIGURE 7

CaS‐based nanoplatform for Ca²⁺ overload. (A) Schematic illustration of the preparation process of ZnPP@PAA‐CaS and (B) ZnPP@PAA‐CaS mediated Ca²⁺ overload and signalling cascade antitumour immunotherapy. (C) characterization of ICD. (D) The polarization of macrophages. (1) blank; (2) PAA‐Ca; (3) ZnPP; (4) PAA‐CaS; (5) ZnPP@PAA‐CaS. (E) Digital photos of metastatic nodules in lungs after different treatments and corresponding H&E staining images. All groups: (1) blank; (2) PAA‐Ca; (3) ZnPP; (4) αPD‐1; (5) PAA‐CaS; (6) ZnPP@PAA‐CaS; (7) PAA‐CaS + αPD‐1; (8) ZnPP@PAA‐CaS + αPD‐1. Reproduced with permission.^{[ 71 ]} Copyright 2021, American Chemical Society.

FIGURE 8

CaF₂‐based nanoplatform for Ca²⁺ overload. (A) Schematic illustration for the underlying mechanism of US‐amplified CaF₂ nanozyme for Ca²⁺‐overload‐assisted catalytic tumour therapy. (B) Intracellular Ca²⁺ ions in 4T1 cancer cells and H22 cancer cells. (C) H&E, Ki‐67, and TUNEL staining images of 4T1‐tumour and H22‐tumour sections from the tumour‐bearing mice in different treatment groups. Reproduced with permission.^{[ 76 ]} Copyright 2019, John Wiley & Sons.

FIGURE 9

Other forms of Ca²⁺‐based nanomaterials for Ca²⁺ overload (CaxCoO₂). (A) Schematic diagram of the synthesis procedure of CCO@ss‐SiO₂‐Ce6 and (B) tumour therapy of synergistic induction of CCO@ss‐SiO₂‐Ce6 heat‐enhanced Ca²⁺ overload and PDT/PTT. (C) Intracellular ROS generation in HepG2 cells treated with CCO@ss‐SiO₂‐Ce6 under 660 nm laser irradiation. (D) Cell viability of HepG2 cells after incubated with different concentrations of CCO@ss‐SiO₂‐Ce6. (E) Tumour volume, (F) body weight, and (G) H&E staining images of tumour slices from mice treated with various treatments after 15 days. Reproduced with permission.^{[ 77 ]} Copyright 2021, American Chemical Society.

FIGURE 10

Other forms of Ca²⁺‐based nanomaterials for Ca²⁺ overload (Ca²⁺‐based MOF). (A) Schematic illustration for the synthesis process of PCa and (B) mechanism of PCa for amplified Ca²⁺ overload and activated immunotherapy. Fluorescent images to detect the (C) intracellular Ca²⁺ concentration and (D) ROS generation. (E, F) BMDC maturation analysis by flow cytometry. (G) Tumour growth curves and (H) photographs of collected tumours at the end of treatment after various treatments. Reproduced with permission.^{[ 78 ]} Copyright 2023, American Chemical Society.

FIGURE 11

Plasma membrane damage to trigger Ca²⁺ overload. (A) Schematic diagram of the preparation process of CMA‐nPS and (B) their capacity to generate abundant ROS and introduce intracellular Ca²⁺ overload for enhanced antitumour efficiency. (C) Fluorescent images to detect cell membrane integrity and (D) intracellular Ca²⁺ concentration. (E) TEM images of H1299 cells after different treatments to observe mitochondrial integrity. (F) H&E and TUNEL staining images of H1299 tumour‐bearing mice after different treatments. Reproduced with permission.^{[ 79 ]} Copyright 2022, John Wiley & Sons.

FIGURE 12

NO to trigger Ca²⁺ overload. (A) Schematic illustration of intracellular calcium stores modulated by NO for Ca²⁺ overload‐initiated cancer therapy. (B) Aggregation quenching effect of 2 nitroimidazole (2nIm) molecules (top). The photochemical activity of 2nIm could be improved by ZIF‐82 (low). (C) Mechanisms of NO activating RyRS. Fluorescent images to detect (D) intracellular Ca²⁺ concentration and (E) ROS generation. Reproduced with permission.^{[ 82 ]} Copyright 2021, John Wiley & Sons.

FIGURE 13

PA chelating to capture Ca²⁺ for Ca²⁺ inhibition. (A) Schematic illustration of the synthesis of CePA and their antitumour mechanism through PA‐chelated Ca²⁺ for overcoming drug resistance and chemotherapy. (B, C) Intracellular Ca²⁺ concentration after different treatments. (D) H&E staining and (E) immunofluorescence staining of ROS, (F) P‐gp and Dox. Reproduced with permission.^{[ 90 ]} Copyright 2022, Springer.

FIGURE 14

EGTA chelating to capture Ca²⁺ for Ca²⁺ inhibition. (A) Schematic illustration of the synthesis of AEPF NPs and their antitumour performance via EGTA‐captured Ca²⁺ and photothermal therapy. (B) TEM images of AEPF NPs in Ca²⁺ solution before adding esterase. (C) TEM images of AEPF NPs in Ca²⁺ solution after adding esterase. (D) UV–vis spectrum and corresponding photographs of AEPF NPs solution with and without Ca²⁺ and esterase. (E) H&E and Ki‐67 staining images of tumour sections in different treatment groups. Reproduced with permission.^{[ 94 ]} Copyright 2021, Elsevier.

FIGURE 15

Knockdown of T‐type Ca²⁺ channel for Ca²⁺ inhibition. (A) Schematic illustration of the synthesis process of MSNCs and their application in tumour therapy through downregulation of T‐type Ca²⁺ channel expression, reduction in intracellular Ca²⁺ concentration, and chemotherapy. Fluorescent images to detect (B) Ca_v 3.1 and Ca_v 3.2 T‐type Ca²⁺ channels and (C) intracellular Ca²⁺ concentration. (D) H&E and TUNEL staining images of tumour sections after different treatments. Reproduced with permission.^{[ 23 ]} Copyright 2019, American Chemical Society.

FIGURE 16

Ca²⁺ inducing ICD of cancer cells to produce tumor‐associated antigens. (A) Schematic illustration of US‐augmented collaborative Ca²⁺ overload and immunotherapy utilizing PEGCaCUR. (B) Fluorescent images to detect mitochondrial membrane potential. (C) Immunofluorescence staining of intratumoural CD4 (red fluorescence) and CD8 (green fluorescence) T cells after different treatments. (D) H&E and TUNEL staining images of tumour sections after different treatments. (E) H&E‐staining of lung sections at the end of different treatments. Tumour metastasis was indicated by red arrows. Reproduced with permission.^{[ 29 ]} Copyright 2021, American Chemical Society.

FIGURE 17

Ca²⁺ mediating autophagy of DCs to promote the presentation of antigens. (A) Schematic illustration of HOCN overcoming multiple barriers in DCs’ antigen cross‐presentation for chemo‐immunotherapy by neutralizing tumour acidity, inducing autophagy in DCs, and promoting Ca²⁺ overload to enhance DAMPs released from tumour cells. (B) Tumour growth curves and (C) representative tumour tissues from each group after different treatments. (D) DC maturation rates and (E) CD⁸⁺ and CD⁴⁺ T lymphocytes were examined by flow cytometry. Reproduced with permission.^{[ 30 ]} Copyright 2020, American Chemical Society.

FIGURE 18

Ca²⁺ functioning as a vaccine adjuvant to enhance T cell responses. (A) Schematic illustration of the fabrication of Fe/Se‐CaP nanohybrid and their antitumour mechanisms involving GSH depletion, ROS generation, and vaccine adjuvant functions. Fluorescent images to detect (B) intracellular GSH level and (C) ROS generation. (D) Western blotting of apoptosis‐associated proteins. (E) Schematic illustration of the cell apoptosis mechanism. (F) Immunofluorescence staining of intratumoural CD4 (yellow fluorescence) and CD8 (red fluorescence) T cells after different treatments. Intratumoural IL‐12p70 (G), IFN‐γ (H), and TNF‐α (I) expression examined by enzyme‐linked immunosorbent assay (ELISA). Reproduced with permission.^{[ 113 ]} Copyright 2022, Elsevier.

FIGURE 19

Ca²⁺ regulation of macrophage M1 polarization. (A) Schematic illustration of the synthesis of OMV@CaP. (B) Ca²⁺ release profile at different pH values. (C) pH value changes inside tumour tissues after different treatments. (D) Macrophage polarization analysis by flow cytometry. Intratumoural (E) IL‐12, (F) IL‐6, (G) TNF‐α, and (H) IFN‐γ expression were examined by ELISA. Reproduced with permission.^{[ 123 ]} Copyright 2020, John Wiley & Sons.