Table 2.
Metformin-based nanomedicines reprogram the tumor microenvironment
| Material type | Nanoformulation | Function | Combination therapy | Indication | Refs. |
|---|---|---|---|---|---|
| Peptide-based nanoparticle | MA-pepA-Ce6 | MMP-2 responsiveness; αvβ3-mediated tumor targeting; downregulation of PD-L1 expression | PDT | Breast cancer | 122 |
| Polymeric Nanoparticle | HA-CDDP/PMet | Hyaluronic acid-mediated tumor targeting; reversal of chemotherapy resistance; inducing tumor cell apoptosis | Chemotherapy | Lung cancer | 123 |
| aPD-L1-PolyMet/BPN | Anti-PD-L1 antibody-mediated tumor targeting; inhibiting primary and abscopal tumor growth and metastasis | PTT; chemotherapy and immunotherapy | Breast cancer | 124 | |
| LPH-PolyMet-siVEGF | Inducing tumor cell autophagy and apoptosis through downregulating mTOR; decreasing VEGF production | Gene therapy | Non-small-cell lung cancer | 125 | |
| TA-Met@MS | Pulsed release of metformin and tumor antigens; promoting FAO and memory phenotype differentiation of CD8+ T cells | PTT | Breast cancer and melanoma | 126 | |
| Metformin-loaded PLGA-PEG NPs | Inhibition of mTOR and reduction in telomerase reverse transcriptase expression; G1 phase arrest; inducing apoptosis | -- | Breast cancer | 127 | |
| Met-loaded FA-PLGA-PEG NPs | Folate-mediated tumor targeting; upregulating the expression of pro-apoptotic Bax, Caspase 7, Caspase 3, p53 and anti-apoptotic Bcl-2 | -- | Breast cancer | 128 | |
| Polymet | Sensitization of anti-PD-L1 antibody; increasing IFN-γ production and infiltration of T cells; increasing anti-tumor intestinal microbes | -- | Colorectal cancer | 129 | |
| Micelle | FucOMDs | Fucoidan-mediated premetastatic site targeting; inhibition of adhesion of CTCs to endothelial cells; downregulating the expression of fibronectin and MMP-9 | Chemotherapy | Breast cancer | 130 |
| PMD | Downregulating PD-L1 expression; inhibiting Treg cell suppressive activity; promoting DC maturation | Chemotherapy; Immunotherapy | Breast cancer | 131 | |
| Liposome | IR775@Met@Lip | Reversal of hypoxia and enhancing PDT; downregulating PD-L1 expression; enhancing IFN-γ secretion and infiltration of CD8+ T cells | PDT | Colorectal cancer | 132 |
| Met-HCe6-Liposome | Sustainable release of metformin in tumor cells; improving hypoxia | PDT | Colorectal cancer | 133 | |
| Met-oxa (IV)-liposome | Relieving hypoxia; repolarizing TAMs to an M1 phenotype | Chemotherapy; Immunotherapy | Colorectal cancer | 134 | |
| Hydrogel | D@HPMNG | GSH responsiveness; hyaluronic acid-mediated tumor targeting; repolarization of TAMs to an M1 phenotype; enhancing DC maturation and CD8+ T cell infiltration | Chemotherapy | Melanoma | 135 |
| CAR-T@Met/gel | Sustain release of CAR-T cells and metformin; inhibiting glycolysis and OXPHOS in tumor cells; upregulating ACSS1 expression and promotion of OXPHOS and memory phenotype differentiation in CAR-T cells | Immunotherapy | Gastric carcinoma | 67 | |
| PMI | Reshaping an M2-like TAM phenotype; downregulating PD-L1 expression in tumor cells; enhancing the infiltration of CD8+ T cells | Immunotherapy | Breast cancer | 136 | |
| MCGPD/RGD NPs | MMP-2 responsiveness; RGD peptide-mediated tumor cell targeting; improving the hypoxia; reducing ATP production | PDT; PTT and chemotherapy | Breast cancer | 137 | |
| Extracellular vesicles | Met@HMnER | Oxygen generation and hypoxia alleviation; sensitizing radiotherapy; G2/M phase arrest; activating the cGAS-STING pathway | Radiotherapy | Breast cancer | 138 |
| SPI@hEL-RS17 NPs | RS17 peptide-mediated tumor targeting; inhibiting pyruvate kinase-M2 and damaging mitochondria; enhancing macrophage phagocytosis | PDT and chemotherapy | Breast cancer and melanoma | 139 | |
| Met@Man-MP | Mannose-mediated M2-like TAM targeting; repolarization of TAMs to an M1 phenotype; recruitment of CD8+ T cells; reducing immunosuppressive MDSCs and Treg cells | Immunotherapy | Hepatocellular carcinoma | 140 | |
| Inorganic material | CS-metformin@MnO2 | pH-responsive release; downregulating PD-L1 expression; promoting wound healing | -- | Breast cancer | 141 |
| HMMDN-Met@PM | GSH and pH responsiveness; peptide-mediated M2-like TAM targeting; repolarization of TAMs to an M1 phenotype; MR imaging | -- | Breast cancer | 142 | |
| NMC + NTC | Aptamer and magnetics-mediated tumor targeting; downregulating the expression of HK2 and PD-L1; inhibition of glycolysis; alleviating hypoxia; dual modality imaging | PTT; PDT and Immunotherapy | Hepatocellular carcinoma | 143 | |
| Met@BF | pH-responsive charge reversal; downregulation of PD-L1 expression; inducing DC maturation | CDT | Melanoma | 144 | |
| Mn-MSN@Met-M NPs | GSH and pH responsiveness; homologous tumor cell targeting; stabilizing the STING protein and activating the cGAS-STING pathway | Immunotherapy | Lung cancer | 145 |
ACSS1: Acyl-CoA synthetase short chain family member 1; CAR-T: chimeric antigen receptor T cell; cGAS-STING: cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes; PD-L1: programmed cell death 1 ligand 1; DC: dendritic cell; CDT: chemodynamic therapy; FAO: fatty acid oxidation; PTT: photothermal therapy; MMP-2: matrix metalloproteinase-2; PDT: photodynamic therapy; GSH: glutathione; TAM: tumor-associated macrophage; CTCs: circulating tumor cells; HK2: hexokinase 2; OXPHOS: oxidative phosphorylation; MDSC: myeloid-derived suppressor cell; Treg: regulatory T cell.