Immune-regulating bimetallic metal-organic framework nanoparticles designed for cancer immunotherapy

Abstract

Immunogenic cell death (ICD) is a promising strategy in cancer immunotherapy to induce high immunogenicity and activate the immune system. However, its efficacy is counteracted by the concurrent exposure of phos- phatidylserine (PS), an immunosuppressive signal on the surface of cancer cells. Here we report the synthesis of a bimetallic metal-organic framework (MOF) nanoparticle containing Gd3+ and Zn2+ (Gd-MOF-5) that can be used as an immunomodulator to downregulate the immunosuppressive PS signal and an ICD inducer to upregulate immunostimulatory signals. Gd3+ inhibits PS externalization via inhibiting the activity of scramblase, an enzyme to transfer PS to the outer leaflet of plasma membrane. Moreover, intracellular Zn2+ overload activates endo- plasmic reticulum stress for ICD induction. In combination with an immune checkpoint inhibitor (PD-L1 anti- body, denoted as aPDL1), Gd-MOF-5 activated potent immune response and effectively inhibited primary and distal tumor growth in a bilateral 4T1 tumor model. This work presents a new strategy using designed MOF materials to modulate the cell signalling and immunosuppressive microenvironment to improve the outcome of cancer immunotherapy.