Abstract
The combination of an immuno-metabolic adjuvant and immune checkpoint inhibitors holds great promise for effective suppression of tumor growth and invasion. In this study, a pH-responsive co-delivery platform was developed for metformin (Met), a known immuno-metabolic modulator, and short interfering RNA (siRNA) targeting fibrinogen-like protein 1 mRNA (siFGL1), using a hybrid biomimetic membrane (from macrophages and cancer cells)-camouflaged poly (lactic-co-glycolic acid) nanoparticles. To improve the endo-lysosomal escape of siRNA for effective cytosolic siRNA delivery, a pH-triggered CO2 gas-generating nanoplatform was developed using the guanidine group of Met. It can react reversibly with CO2 to form Met-CO2 for the pH-dependent capture/release of CO2. The introduction of Met, a conventional anti-diabetic drug, promotes programmed death-ligand 1 (PD-L1) degradation by activating adenosine monophosphate-activated protein kinase, subsequently blocking the inhibitory signals of PD-L1. As a result, siFGL1 delivery by the camouflaged nanoparticles of the hybrid biomimetic membrane can effectively silence the FGL1 gene, promoting T-cell-mediated immune responses and enhancing antitumor immunity. We found that a combination of PD-L1/programmed death 1 signaling blockade and FGL1 gene silencing exhibited high synergistic therapeutic efficacy against breast cancer in vitro and in vivo. Additionally, Met alleviated tumor hypoxia by reducing oxygen consumption and inducing M1-type differentiation of tumor-related macrophages, which improved the tumor immunosuppressive microenvironment. Our results indicate the potential of hybrid biomimetic membrane-camouflaged nanoparticles and combined Met-FGL1 blockade in breast cancer immunotherapy.
Highlights
Immunotherapy is a groundbreaking therapeutic approach that provides unparalleled opportunities to significantly improve the treatment of various diseases, including cancer [1,2,3]
Synthesis and characterization of MC‐PLGA@ Met‐CO2‐siFGL1 NPs Met-CO2 was produced by bubbling an aqueous solution of Met for 1 h with C O2
We further investigated the intracellular distribution of Fluorescein amidite (FAM)-siFGL1 mediated by MC-PLGA@Met-CO2/FAM-siFGL1 NPs using 3D Confocal laser scanning microscopy (CLSM) images
Summary
Immunotherapy is a groundbreaking therapeutic approach that provides unparalleled opportunities to significantly improve the treatment of various diseases, including cancer [1,2,3]. Programmed death ligand-1 (PD-L1) is a well-studied immune checkpoint inhibitor of programmed death 1 (PD-1), a T-cell negative regulator, and is upregulated on the surface of solid tumors, including breast cancers [2, 9]. Recent studies have demonstrated that Met can regulate the differentiation and activity of T cells via an intrinsic pathway [15] to promote PD-L1 degradation and activate AMPK, and subsequently block PD-L1/PD-1 signaling [16]. These studies illustrate that the anticancer mechanism of Met is immune-mediated. Met has the potential to improve the therapeutic outcomes of immunotherapy by blocking PD-L1/PD-1 signaling
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