Photonic control of image-guided ferroptosis cancer nanomedicine

Abstract

Photonic nanomaterials, characterized by their remarkable photonic tunability, empower a diverse range of applications, including cutting-edge advances in cancer nanomedicine. Recently, ferroptosis has emerged as a promising alternative strategy for effectively killing cancer cells with minimizing therapeutic resistance. Novel design of photonic nanomaterials that can integrate photoresponsive-ferroptosis inducers, -diagnostic imaging, and -synergistic components provide significant benefits to effectively trigger local ferroptosis. This review provides a comprehensive overview of recent advancements in photonic nanomaterials for image-guided ferroptosis cancer nanomedicine, offering insights into their strengths, constraints, and their potential as a future paradigm in cancer treatment.

Keywords: Cancer therapy; Coordination nanomedicine; Ferroptosis; Image-guided therapy; Photonic nanomaterials.

Fig. 1.

Schematic illustrations of various photonic nanomaterials, their photonic manipulation including photothermal therapy (PTT), photodynamic therapy (PDT) upon NIR irradiation, light-triggered release, various imaging modalities for image-guided synergistic ferroptosis cancer nanomedicine. UCNM: Upconversion nanomaterial, MOF: Metal-organic framework.

Fig. 2.

Versatile photonic nanomaterials for ferroptosis nanomedicine. Photonic nanomaterials directly participate in ferroptosis via PTT and PDT, triggers a local release of FIAs, and hold a promise as multi-modal image guided ferroptosis cancer nanomedicine. LSPR: localized surface plasmon resonance.

Fig. 3.

NIR-triggered ferroptosis nanomedicine. (a) SPN-M synthesis. TEM images of (b) SPN-0 and (c) SPN-M1, and (d) STEM image of SPN-M1. (e) H₂O₂-supported SPN-M1 reaction under acidic conditions. (f) The therapeutic effects of SPN-M1 upon laser irradiation. (g) Live/dead cell staining of 4T1 cells after incubation with the SPN and irradiation with an 808 nm laser using calcein AM and propidium iodine (PI) staining. (h) A confocal image after CM-H₂DCFDA staining. (i) FI results of mice after injecting them with SPN-0 or SPN-M1. (j) Relative tumor volume changes after the injection with SPN-M1, SPN-0, or saline. Reproduced with permission [82].

Fig. 4.

NIR-triggered ferroptosis via photon upconversion. (a) Synthesis of Azo-CA4 and Azo-CA4 for apoptosis and ferroptosis inducement. (b) A TEM image and dynamic light scattering (DLS) spectrum of Azo-CA4. (c) Images of UCNM@LP and Azo-CA4 after laser irradiation. (d) Liperfluo staining of MDA-MB-231 cancer cells after treatment with UCNM@LP and UCNM@LP(Azo-CA4) using 980 nm laser irradiation. Changes in (e) tumor mass, (f) tumor volume, (g) and Kaplan-Meier survival analysis up to 50 days after the treatment. Reproduced with permission [83].

Fig. 5.

Combinational PDT and ferroptosis induction nanomedicine. (a) A schematic illustration of NSs@DCPy-mediated ferroptosis under light irradiation. (b) The synthesis of vermiculite NSs@DCPy. (c) A TEM image and (d) an AFM image of NSs@DCPy. (e) The height of NSs@DCPy according to the white line. (f) Cell viability after treatment under dark and light conditions. (g) Tumor volume changes after treatment with PBS, NSs, DCPy, and NSs@DCPy. (h) In vivo FI results after treatment of mice with DCPy and NSs@DCPy. The white circles indicate the tumor regions. (i) Images of the major organs in a mouse 24 h post-injection. Li, Liver; S, Spleen; Lu, Lung; K, Kidney; H, Heart; T, Tumor. Reproduced with permission [84].

Fig. 6.

PDT-enhanced ferroptosis inducing nanomedicine. (a) SRF@Hb-Ce6 synthesis and SRF@Hb-Ce6-mediated ferroptosis. (b) Real-time FI results of free Ce6 and SRF@Hb-Ce6 in mice post-injection. (c) FI results of the harvested major organs and tumors. (d) Changes in the tumor growth rate after treatment. (e) The survival rate of mice with various treatment methods. Reproduced with permission [85].

Fig. 7.

Combinational PDT and ferroptosis inducing nanomedicine. (a) A schematic diagram of the production of Ce6-erastin NMs and their mediation of ferroptosis. (b) DLS data and (c) TEM image of the Ce6-erastin NMs. (d) FI results of mice after intravenous injection of free Ce6 or Ce6-erastin NMs. (e) Tumor reduction percentage post-injection. (f) Tumor growth analysis after the 30 days after injection of saline, free Ce6, free erastin, a mixture of free Ce6/erastin, or Ce6-erastin NMs with and without laser irradiation. Reproduced with permission [86].

Fig. 8.

Photo-triggered release of FIAs. (a) Schematic illustrations of BNP@R synthesis and BNP@R-mediated ferroptosis combined with immunotherapy. (b) The survival rate of mice after treatment (n = 5). (c) Quantification of lung metastasis by 4T1 cells via flow cytometry analysis (n = 5). (d) Bioluminescence imaging of orthotopic 4T1 breast tumor lung metastasis. (e) CD8⁺ and CD4⁺ T lymphocytes from CD3⁺ T cells, (f) CD44⁺CD133⁺ cells from CD45⁻ tumor cells, (g) N-cadherin⁺ cells from CD133⁺CD44⁺CD45⁻ tumor cells, and (h) CD127⁺CD44⁺ central memory T cells from the spleen (*p < 0.05, **p < 0.01, ***p < 0.001). (i) FI results of 4T1 tumor-bearing mice after injection of BNP@R and NP@R (n = 3). Reproduced with permission [87].

Fig. 9.

Ferroptosis-accelerating PTT nanomedicine. (a) A schematic of PPy and FePPy NM synthesis and the mechanism of FePPy nanozyme-mediated therapeutic effect. (b) A TEM image and (c) DLS data for the FePPy NMs. (d) PAI using the FePPy and PPy NMs. (e) The measured photoacoustic intensity according to the concentration. (f) PAI results of tumors after PPy and FePPy NM injection and 680 nm laser irradiation. (g) A bar chart of the obtained photoacoustic signals. (h) IR thermal images after PBS, PPy, or FePPy injection followed by laser irradiation. (i) Quantification of temperature changes obtained from the IR images in (h). (j) Tumor growth curves after treatment. (k) Photograph image, (l) tumor weight, and (m) body weight changes after the treatment. Reproduced with permission [88].

Fig. 10.

Photo-triggered/enhanced ferroptosis nanomedicine. (a) Synthesis of the HSN and its mechanism of action through the photothermal effect and ferroptosis. (b) Real-Time PAI results of 4T1 tumor-bearing mice. (c) Photoacoustic intensity obtained from the images in (b) (n = 3). (d) Temperature increases in HSN and HSN₀ after 1064 nm laser irradiation (n = 3). (e) Tumor growth curves after treatment with PBS, HSN₀, or HSN (n = 3). **p < 0.01, ***p < 0.001 Reproduced with permission [89].

Fig. 11.

Combinational PTT and ferroptosis nanomedicine. (a) Schematics of SPFeN synthesis and SPFeN and photothermal-mediated ferroptosis. (b) DLS data, (c) TEM images, and (d) optical images of SPcN and SPFeN. (e) PAI results of 4T1 tumor-bearing mice. (f) Photoacoustic signals of tumors over time. (g) Thermal images of mice after 5 min of 808 nm laser irradiation. (h) Averaged temperature curves after laser irradiation. (i) Tumor growth curves after treatment. (j) Tumor weight changes after treatment with and without laser irradiation. (*p < 0.05, ***<0.001) Reproduced with permission [90].

Fig. 12.

PTT-mediated ferroptosis nanomedicine. (a) Synthesis of 17-DMAG-HMPB@sPP@HA NMs. (b) The mechanism of action of the 17-DMAG-HMPB@sPP@HA after being internalized by tumor cells. (c) TEM images of 17-DMAG-HMPB@sPP@Ha. (d) DLS data of PB, HMPB, 17-DMAG-HMPB@sPP and 17-DMAG-HMPB@sPP@HA. (e) Live/dead cell analysis with Calcein AM and PI. Laser irradiation was conducted for 5 min. (f) Thermal images of B16 tumor-bearing mice after 808 nm laser irradiation. (g) Temperature vs. laser irradiation time. (h) Tumor growth rate changes after various treatment regimens (n = 5, *p < 0.05, **p < 0.01). Reproduced with permission [91].

Fig. 13.

Photo-responsive nanozyme-mediated ferroptosis. (a) Pd SAzyme construction and the ferroptosis-mediated therapeutic process. (b) A TEM image of Pd SAzyme. (c) Temperature changes with and without laser irradiation, (d) tumor growth curves, and (e) final tumor weights after various treatment methods (*p < 0.05, **p < 0.01, ***p < 0.001). Reproduced with permission [92].

Fig. 14.

FI/PAI-guided ferroptosis and DC maturation using coordination PFG MPNs. (a) The mechanism for coordination PFG MPN-mediated therapy upon laser irradiation. (b) FI results of tumor-bearing mice. (c) PAI results and (d) thermal images of the tumor regions in mice. (e) Tumor volume and (f) quantification of T cells at the primary and distant tumor sites after treatment. Reproduced with permission [93].

Fig. 15.

PDT-triggered ferroptosis and M2-M1 macrophage polarization. (a) The ferrihydrite-mediated therapeutic effect comprising ferroptosis and immunotherapy. (b) A TEM image and elemental mapping images of PEG-Fns. (c) TNF-α and (d) IL-10 measurement after culturing RAW264.7 macrophage with CSS-7 cells, PEG-Fns, or CSS-7 cells and PEG-Fns. (e) A photograph of a tumor and (f) tumor weight after treatment for 14 days (n = 5). (g) Images of 4T1 tumor-bearing mice 0, 3, 7, and 14 days after treatment. 48 h after injecting PEG-Fns, the mice were irradiated with blue light for 30 min; the treatment was repeated 7 days later (**p < 0.01). Reproduced with permission [160].

Fig. 16.

PTT-triggered ferroptosis and enhanced immunogenic cell death. (a) TPA-NDTA synthesis and combinational therapy using RSL3 and TPA-NDTA NM-mediated ferroptosis. (b) A TEM and DLS data for the TPA-NDTA NMs. (c) Photoacoustic signal amplitude according to the NM concentration. (d) Relative photoacoustic intensities of indocyanine green (ICG) and TPA-NDTA NMs. (e) Tumor growth rate and (f) survival rate after treatment with RSL3, PHT, RSL3 + PHT, or DFO + RSL3 + PHT. (g) Volume changes in metastasized tumors after various treatment regimens (***p < 0.001). Reproduced with permission [161].

Fig. 17.

UCNM-mediated cancer ferroptosis and anti-tumor immunity. (a) Schematic diagram of ferroptosis supported by laser irradiation and immunotherapy. TEM images of (b) UCNM@mSiO₂ NMs, (c) UCNM@mSiO₂@liposome and (d) UCB. (e) Live/dead cell staining of B16/F10 cancer cells after treatment with PBS, UC, or UCB with or without laser irradiation, (f) tumor volume, and (g) tumor size variation 15 days after treatment with various methods. Quantification of (h) cytotoxic T lymphocytes, (i) CD3⁺CD8⁺CD107a⁺ lymphocytes, and (j) CD45⁺ leukocytes in tumors. (k) The level of IL-12p40 and IFN-γ (proinflammatory cytokines) 15 days after treatment (*p < 0.05, **p < 0.01, ***p < 0.001). Reproduced with permission [162].

Fig. 18.

Combinational PTT/ferroptosis-mediated macrophage polarization. (a) Schematics of the synthesis process and mechanism of photonic nanocomposite gel. (b) A TEM image and absorbance data of AuNRs. (c) A TEM image and size of iron oxide NMs. (d) A photograph of photonic nanocomposite gelshowing the optimal viscosity of the gel. (e) The increase in temperature caused by the photonic nanocomposite gel upon irradiation. (f) Live/dead cell staining to examine the photothermal effect of the AuNRs upon NIR laser irradiation. (g) Cell viability after treatment. (h) Counts of M1-like macrophages. (i) The tumor growth rate after treatment (*p < 0.05, **p < 0.01). Reproduced with permission [94].

Fig. 19.

LI-guided ferroptosis cancer nanomedicine via 2-dimensional coordination nanosheets. (a) A schematic illustration of the mode of action of Ir-g-C₃N₄-mediated tumor therapy. (b) LI results of major organs and tumors 6, 12, and 24 h after treatment. H, Heart; Li, Liver; S, Spleen; Lu, Lung; K, Kidney; T, Tumor. (c) Tumor growth curves after various treatment regimens (Group i: saline, Group ii: saline + light, Group iii: g-C₃N₄ + light, Group iv: Ir-g-C₃N₄, and Group v: Ir-g-C₃N₄ + light). *p < 0.05, **p < 0.01, ***p < 0.001. Reproduced with permission [95].

Fig. 20.

LI-guided/photo-triggered coordination ferroptosis cancer nanomedicine. (a) Schematic illustration of the IrS coordination NM synthesis and their mechanisms that induce ferroptosis and apoptosis of cancer cells. (b) A TEM image of IrS coordination NM after the addition of GSH. (c) Lifetime analysis of the IrS coordination NMs with and without the addition of GSH. (d) LI results of A549 cells after Ir-SH and IrS coordination NM internalization. (e) LI results of major organs and tumors according to time. H, Heart; Li, Liver; Sp, Spleen; Lu, Lung; Ki, Kidney; T, tumor. (f) Luminescence intensity obtained from (e). (g) The tumor growth rates and (h) photographs of the harvested tumors after various treatment regimens. Reproduced with permission [96].

Fig. 21.

PAI-guided charge-transfer complexes-mediated ferroptosis. (a) Schematic diagrams of TMB-F4TCNQ and TMB-TCNQ synthesis and the ferroptosis and photothermal-mediated therapeutic mechanism of TMB-F4TCNQ. TEM images of (b) TMB-TCNQ and (c) TMB-F4TCNQ. (d) Live/dead cell staining after TMB-F4TCNQ and laser treatment. (e) PAI results of tumors after injection and 1300 nm laser irradiation. (f) IR thermal images of mice after injection and 1060 nm laser irradiation. Reproduced with permission [97].

Fig. 22.

PAI/FI-guided ferroptosis cancer nanomedicine. (a) The anticancer mechanism of MH-PLGA-IR780. (b) FI results of tumor-bearing mice. (c) PAI results and intensities according to the concentration of NMs. (d) Photoacoustic intensity graphs and (e) PAI results after administering PLGA-IR780 and MH-PLGA-IR 780 (n = 5, *p < 0.05, **p < 0.01). Reproduced with permission [98].

Fig. 23.

FI-guided triggered release of FIAs using coordinated MOF. (a) The coordinated MOF production process and the mechanism of MOF-mediated ferroptosis and apoptosis. TEM image of (b) Ce6@CMOF and (c) Ce6@RMOF. (d) The sizes of CMOF, RMOF, Ce6@CMOF, and Ce6@RMOF, from TEM images. (e) FI result of tumor-bearing mice after the injection of Ce6, Ce6@CMOF, or Ce6@RMOF. (f) FI result of the major organs and tumors 24 h post-injection. (g) Fluorescent intensity signals from tumors. (h) Tumor volume after treatment with PBS, Ce6, Ce6@CMOF, or Ce6@RMOF (*p < 0.05, **p < 0.01, ***p < 0.001). Reproduced with permission [67].

Fig. 24.

FI-guided photonic ferroptosis cancer nanomedicine. (a) BCFe@SRF synthesis and BCFe@SRF-mediated ferroptosis with PDT. TEM images of (b) BSA-Ce6, (c) BCFe@SRF, and (d) degradation of BCFe@SRF. (e) Live/dead cell staining after various treatment regimens. (f) FI of tumor-bearing mice after BCFe@SRF injection. (g) FI result of the major organs and tumors 6 h after injecting BCFe@SRF. Changes in (h) tumor volume and (i) tumor image after treatment. (*p < 0.05, **p < 0.01, ***p < 0.001) Reproduced with permission [99].

Fig. 25.

CT/MRI-guided ferroptosis cancer nanomedicine. (a) Schematic diagrams of synthesis and therapeutic mechanism of CISAR. TEM images of (b) MSN NMs, (c) CIS NMs, and (d) CISA NMs. Relative tumor volume changes in (e) primary and (f) distant tumors after treatment. (g) The IFN-γ level 21 days after treatment. (h) Thermal images of tumor-bearing mice after injection of the CISAR NMs followed by 1064 nm laser irradiation. (i) PAI results of tumor-bearing mice 0, 1, 3, 6, 12, and 24 h after injection. (j) MRI results and T₂ values corresponding to the concentration of CISAR NMs. (k) MRI results of mice after CISAR NM injection according to time. (l) CT images and intensities according to the concentration of CISAR NMs. (m) CT images of tumor-bearing mice 6 h after injection of PBS and CISAR NMs. Reproduced with permission [100].

Fig. 26.

US/MRI-guided ferroptosis cancer therapy using coordinated PFP@Fe/Cu-SS MOF. (a) Schematic illustrations of the synthesis process and mechanism of action of the PFP@Fe/Cu-SS MOF. (b) In vitro US images of the Fe/Cu-SS and PFP@Fe/Cu-SS MOFs upon NIR laser irradiation. (c) In vivo US images of the PFP@Fe/Cu-SS MOF under NIR irradiation. (d) T₁-weighted MRI results and (e) r₁ values of FeCl₃-6H₂O (Fe³⁺), CuCl₂-2H₂O (Cu²⁺), and the PFP@Fe/Cu-SS MOF. (f) T₁-weighted MRI results of tumor-bearing mice after injection of the PFP@Fe/Cu-SS MOF. The tumor is indicated by the red dotted circle. (g) Thermal images of mice after NIR laser irradiation. (h) Temperature changes after PFP@Fe/Cu-SS MOF injection and NIR laser irradiation. (i) Tumor volume changes after treatment (*p < 0.05, **p < 0.01, ***p < 0.001). Reproduced with permission [101].

Fig. 27.

PAI-guided combinational chemotherapy and ferroptosis nanomedicine. (a) A schematic illustration of DFHHP-mediated cancer therapy. (b) PAI results of FHHP treatment with and without GSH. (c) PAI results of the muscle and tumor sites after injection of FHHP followed by US irradiation. (d) Temperature changes upon US irradiation. (e) Tumor weight changes after various treatments regimens (n = 5, *p < 0.05, **p < 0.01, ***p < 0.001). Reproduced with permission [102].

Fig. 28.

FI-guided/photo-triggered ferroptosis nanomedicine combined with chemotherapy. (a) A schematic illustration of the CSO-SS-Cy7-Hex/SPION/SRF-mediated treatment mechanism. (b) The tumor growth curves of tumor after treatment with saline, CSO-SS-Cy7-Hex, CSO-SS-Cy7-Hex/SPION, CSO-SS-Cy7-Hex/SRF, CSO-SS-Cy7-Hex/SPION/SRF, or CSO-SS-Cy7-Hex/SPION/SRF with NIR irradiation. (c) NIR FI results of tumor-bearing mice after injection of CSO-SS-Cy7-Hex/SPION/SRF (c) with and (d) without applying a magnetic field. Reproduced with permission [103].

Fig. 29.

MRI-guided combinational radiation therapy and ferroptosis nanomedicine. (a) Schematic diagrams of the synthesis and therapeutic mechanism of the SPIONCs. (b) A schematic of SPIONC delivery to the tumor sites. (c) MRI results of major organs and tumors 2 h after injection of SPIONCs. (d) T₂-weighted MRI results of tumor-bearing mice after intravenous or intratumoral injection of SPIONCs. (e) Signal enhancement provided by the SPIONCs over time. (e) T₁-weighted MRI results of treated mice over time. (f) Relative tumor volume and (g) weight after treatment (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). Reproduced with permission [104].

Fig. 30.

MRI/PAI-guided ferroptosis cancer nanomedicine. (a) A schematic diagram of the MMP-2 activatable photothermal-boostable ferroptosis nanomedicine. (b) A TEM image of MMP-2 dependent disassembly of Fe₃O₄@Cu_1.77Se-PEG. (c) A schematic of the Fe₃O₄@Cu_1.77Se-PEG-induced ferroptosis mechanism. (d) T₂-weighted MRI and (e) PAI of Fe₃O₄@Cu_1.77Se-PEG with and without MMP-2 treatment. (f) In vivo ferroptosis-mediated immunotherapy. (g) Tumor growth curves of primary and distant tumors after treatment. (h) Quantification of GPX4, caspase-3, LPO, and immune cell characterization after treatment. Reproduced with permission [105].