Dynamic tagging to drive arginine nano-assembly to metabolically potentiate immune checkpoint blockade therapy

Abstract

L-arginine metabolism is essential for the activation, survival, and effector function of the T lymphocytes and critical in eliminating tumors via T-cell-mediated immunotherapy, such as immune checkpoint blockade (ICB). Unfortunately, efficient delivery of hydrophilic L-arginine to the tumor microenvironment (TME) has met tremendous difficulties because of the limited loading efficacy and rapid diffusion. Inspired by the small-molecule prodrug nanoassemblies with ultrahigh drug-loading, we screen out aromatic aldehydes compounds to be used as dynamic tags to decorate L-arginine (reversible imine). Nano-Arginine (ArgNP, 104 nm) was created based on dynamic tag-mediated self-assembly. Molecular dynamics simulations indicate that the driving force of this self-assembly process is intermolecular hydrogen bonds, π–π stacking, and cation–π interactions. Notably, ArgNP metabolic synergy with anti-PD-L1 antibody (aPDL1) can promote tumor-infiltrating T cells (3.3-fold than aPDL1), resulting in a tumor inhibition ratio of 2.6-fold than aPDL1. Besides, such a strategy efficiently reduces the myeloid-derived suppressor cells, increases the M1-macrophages against the tumor, and induces the production of memory T cells. Furthermore, this synergistic therapy effectively restrains lung metastasis and prolongs mouse survival (60% survival ratio). The study highlights the dynamic tags strategy with facility and advance to deliver L-arginine that can metabolically promote ICB therapy.