Macrophage Membrane-Coated Nano-Gemcitabine Promotes Lymphocyte Infiltration and Synergizes AntiPD-L1 to Restore the Tumoricidal Function

Abstract

The limited lymphocyte infiltration and exhaustion of tumoricidal functions in solid tumors remain a formidable obstacle to cancer immunotherapy. Herein, we designed a macrophage membrane-coated nano-gemcitabine system (MNGs) to promote lymphocyte infiltration and then synergized anti-programmed death ligand 1 (antiPD-L1) to reinvigorate the exhausted lymphocytes. MNGs exhibited effective intratumor-permeating and responsive drug-releasing capacity, produced notable elimination of versatile immunosuppressive cells, and promoted lymphocyte infiltration into cancer cell regions in tumors, but over 50% of these infiltrated lymphocytes were in the exhausted state. Compared with MNG monotherapy, the MNGs+antiPD-L1 combination produced 31.77% and 30.63% reduction of exhausted CD3 + CD8 + T cells and natural killer (NK) cells and 2.83-and 3.17-fold increases of interferon-γ (IFN-γ)-positive subtypes, respectively, thereby resulting in considerable therapeutic benefits in several tumor models. Thus, MNGs provide an encouraging strategy to promote lymphocyte infiltration and synergize antiPD-L1 to restore their tumoricidal function for cancer immunotherapy.

Advanced Generation Therapeutics: Biomimetic Nanodelivery System for Tumor Immunotherapy

“…Modifying immune cells through genetic engineering can further enhance the antitumor effect. Li et al designed a PD-L1 functionalized MMs-derived BNDS (MNGs) coating with gemcitabine to promote lymphocyte infiltration, and then cooperated with anti-PD-L1 to reactivate depleted lymphocytes. Based on this, MNGs can accumulate at the site of breast cancer and penetrate into the deep region of cancer, promoting the infiltration of lymphocytes to the intratumoral region by up-regulating the secretion of lymphocyte chemokines.…”

“…Modifying immune cells through genetic engineering can further enhance the antitumor effect. Li et al 81 It is generally believed that NK cells play a vital role in the fight against cancer and infection due to their ability to release cytotoxic factors and mediate apoptosis through receptor activation. With the help of membrane proteins, such as RANKL and DNAM-1, activated NK cells can synthesize and secrete various cytokines to regulate immunity and hematopoiesis and directly kill target cells.…”

Biomimetic Macrophage Membrane-Camouflaged Nanoparticles Induce Ferroptosis by Promoting Mitochondrial Damage in Glioblastoma

“…Recently, increasing attention has been paid to biomimetic drug delivery systems, especially cell membrane-coated nanoparticles (NPs) . Nanoparticles camouflaged by biological cell membranes have recently been the focus of attention for their prolonged circulation in vivo .…”

“…Recently, increasing attention has been paid to biomimetic drug delivery systems, especially cell membrane-coated nanoparticles (NPs). 13 Nanoparticles camouflaged by biological cell membranes have recently been the focus of attention for their prolonged circulation in vivo. 14 Its intrinsic self-recognition properties optimize its dynamic properties by masking its contents to avoid clearance by the mononuclear phagocyte system (MPS) and immune surveillance.…”

A Dual-Mechanism Based Nutrient Partitioning Nanoregulator for Enhanced Immunotherapy against Anti-PD-1 Resistant Tumors

“…Immunotherapy with immune checkpoint inhibitors (ICBs) has exhibited prominent clinical effects in the treatment of various tumors. − However, several challenges such as low response rates and therapeutic resistance still hinder the clinical application. − It has been demonstrated that the immunosuppressive tumor microenvironment (TME) including acidic, hypoxic conditions and immunosuppressive immune cells, causes the relatively poor clinical efficacy of ICBs . Growing evidence has indicated that aerobic glycolysis, characteristic of tumor metabolism, is the leading cause of an immunosuppressive TME .…”