M2 Macrophage Hybrid Membrane‐Camouflaged Targeted Biomimetic Nanosomes to Reprogram Inflammatory Microenvironment for Enhanced Enzyme‐Thermo‐Immunotherapy

Abstract

Excessive inflammatory reactions caused by uric acid deposition are the key factor leading to gout. However, clinical medications cannot simultaneously remove uric acid and eliminate inflammation. An M2 macrophage‐erythrocyte hybrid membrane‐camouflaged biomimetic nanosized liposome (USM[H]L) is engineered to deliver targeted self‐cascading bienzymes and immunomodulators to reprogram the inflammatory microenvironment in gouty rats. The cell‐membrane‐coating endow nanosomes with good immune escape and lysosomal escape to achieve long circulation time and intracellular retention times. After being uptaken by inflammatory cells, synergistic enzyme‐thermo‐immunotherapies are achieved: uricase and nanozyme degraded uric acid and hydrogen peroxide, respectively; bienzymes improved the catalytic abilities of each other; nanozyme produced photothermal effects; and methotrexate has immunomodulatory and anti‐inflammatory effects. The uric acid levels markedly decrease, and ankle swelling and claw curling are effectively alleviated. The levels of inflammatory cytokines and ROS decrease, while the anti‐inflammatory cytokine levels increase. Proinflammatory M1 macrophages are reprogrammed to the anti‐inflammatory M2 phenotype. Notably, the IgG and IgM levels in USM[H]L‐treated rats decrease substantially, while uricase‐treated rats show high immunogenicity. Proteomic analysis show that there are 898 downregulated and 725 upregulated differentially expressed proteins in USM[H]L‐treated rats. The protein‐protein interaction network indicates that the signaling pathways include the spliceosome, ribosome, purine metabolism, etc.

Macrophage membrane-coated nanoparticles for the treatment of infectious diseases

“…Meanwhile, the levels of proinflammatory cytokines (including IL-1β, TNF-α and IL-6) were decreased, and the levels of antiinflammatory cytokine (such as IL-10) was increased in the serum and colonic sites of RMN-treated mice, in comparison with those of the colitis group (figures 6(C) and (D)). Similarly, Chen et al reported that the M2 macrophage and red blood cell hybrid membrane-camouflaged immunomodulator methotrexate could not only effectively promote M2 macrophage polarization but also inhibit the release of inflammatory cytokines [87].…”

“…There are also studies using M2 macrophage membranes for targeted drug delivery due to their ability to home to the parent cells at inflammatory sites. Considering that, Chen et al successfully applied M2 macrophage M-NPs for inflammation-targeted therapy [87].…”

Nanozyme-enhanced ferroptosis for cancer treatment

“…Nanozymes have emerged as effective modulators of the TME, capable of enhancing immunotherapy through diverse mechanisms such as macrophage polarization, antigen presentation, and activation of cellular pathways. 107…”

Nanotechnology in inflammation: cutting-edge advances in diagnostics, therapeutics and theranostics

“…Combining anti-inflammatory and immune-evasive properties of M2 macrophages, the biocompatibility and long circulation of erythrocytes may produce desirable therapeutic efficacy. Most recently, Chen et al developed a novel type of biomimetic nanosized liposome (USM[H]L, 139.2 nm, -13.1 mV) that was coated with hybrid membranes derived from M2 macrophages and erythrocytes 198 . USM[H]L were loaded with uricase and methotrexate, which could synergistically degrade uric acid, scavenge H 2 O 2 , produce photothermal effects and modulate immune responses.…”

“…Upon being injected into a rat model of gouty arthritis (GA), USM[H]L showed enhanced therapeutic effects by reducing uric acid levels, ankle swelling, claw curling, inflammatory cytokines and oxidative stress, while increasing anti-inflammatory cytokines and reprogramming M1 macrophages to M2 phenotype. Notably, USM[H]L also exhibited low immunogenicity and toxicity, as well as high stability and targeting ability, compared to free uricase or other formulations, representing a promising strategy for the treatment of GA and other inflammatory-related diseases 198 .…”