Nanoparticle approaches for manipulating cytokine delivery and neutralization

Abstract

Cytokines are crucial regulators of inflammation and immune tolerance, making them promising targets for treating immune-related diseases like cancer, infections, and autoimmune disorders. While cytokine-based therapies have shown potential, challenges such as dose-limiting toxicity and suboptimal pharmacokinetics have constrained their clinical success. Recent advancements in nanotechnology offer innovative solutions to these limitations, particularly through the use of nanoparticle-based platforms that enhance cytokine delivery and neutralization. This review begins by examining the landscape of cytokine delivery, emphasizing how it can be accomplished using nanoparticle systems encapsulating proteins, DNA or mRNA payloads. We then discuss recent progress on platforms for nanoparticle-based cytokine neutralization, including nanoparticle-antibody complexes and cell membrane-coated nanoparticles. Finally, we highlight the latest clinical developments in cytokine-based therapies employing these strategies before addressing the critical challenges ahead that need to be overcome in order to fully realize the therapeutic potential of nanoparticle-based cytokine manipulation.

Keywords: autoimmune disease; biodetoxification; biomimetic nanoparticle; cytokine delivery; cytokine neutralization; nanodelivery.

Figure 1

Nanoparticle-based strategies for cytokine delivery and neutralization. (A) Nanoparticles can deliver cytokines in the form of protein, DNA, or mRNA. Proteins can be encapsulated for environment-responsive release or surface-immobilized for improved receptor engagement. DNA or mRNA can be protected from degradation while experiencing enhanced localization to the appropriate subcellular compartment. (B) Nanoparticle-based cytokine neutralization strategies include the used of nanoparticle–antibody complexes and cell membrane-coated nanoparticles (CNPs). Created with BioRender.

Figure 2

Cytokine fusion constructs for improved delivery. (A) Immunocytokines formed by fusing the L19 antibody with cytokines such as IL-2, TNF, and IL-12 show selective accumulation in tumor tissues, thus enhancing antitumor immune responses. Adapted with permission (69). Copyright 2020, American Association for the Advancement of Science. (B) IL-2 fused to the von Willebrand factor A3 domain, a collagen-binding domain (CBD), exhibits improved safety and efficacy after delivery by systemic administration. Adapted with permission (73). Copyright 2019, American Association for the Advancement of Science. (C) IL-2 linked to its receptor via a protease-sensitive linker activates only in the tumor microenvironment, enhancing antitumor immune responses. Adapted with permission (75). Copyright 2021, Nature Publishing Group. **p < 0.01.

Figure 3

Surface-anchored cytokines on nanoparticles. (A) IL-2 and anti-CD137 are anchored on stealth liposomes, enabling them to achieve rapid tumor accumulation and enhanced antitumor effects. Adapted with permission (83). Copyright 2018, Nature Publishing Group. (B) IL-12-loaded liposomes are coated with hyaluronic acid (HA) and poly-L-glutamic (PLE) acid through layer-by-layer assembly, and the resulting formulation effectively targets cancer and immune cells. HA-coated liposomes show efficient uptake by cancer cells, while PLE-coated liposomes demonstrate prolonged IL-12 retention at the tumor site. Adapted with permission (85). Copyright 2020, American Chemical Society. (C) Phosphatidylserine liposomes functionalized with IL-10 selectively target microglia and macrophages, enhancing recovery and reducing inflammation after intracerebral hemorrhage. Adapted with permission (87). Copyright 2023, Elsevier. *p < 0.05 and **p < 0.01.

Figure 4

Cytokines encapsulated within nanoparticles. An IL-12 nanocytokine is constructed through the use of pH-sensitive amide bonds and electrostatic interactions, exhibiting higher tumor accumulation and enhanced antitumor effects compared to free IL-12. Adapted with permission (91). Copyright 2023, Wiley-VCH.

Figure 5

Nanoparticle-based cytokine DNA delivery. (A) IL-12 circular single-stranded DNA encapsulated into a folate-targeted lipid nanoparticle can be delivered via intravenous injection for antitumor therapy. Adapted with permission (101). Copyright 2024, Wiley-VCH. (B) An IL-10 plasmid DNA complexed with a nuclear localization signal and encapsulated within a polymeric nanoparticle can be applied for the treatment of rheumatoid arthritis. Adapted with permission (109). Copyright 2024, Elsevier. *p < 0.05 and ****p < 0.0001.

Figure 6

Nanoparticle-based cytokine mRNA delivery. (A) Nanoparticulate IFNγ mRNA delivery can be paired with a mineralized microparticle for synergistic activation of tumor-associated macrophages. Adapted with permission (120). Copyright 2023, Wiley-VCH. (B) IL-2 mRNA delivered via large porous silica nanoparticles by intratumoral injection mediates local cytokine production. Adapted with permission (121). Copyright 2023, American Chemical Society. (C) IL-10 mRNA delivered to atherosclerotic plaques via a mannose-targeted polymeric nanoparticle reduces inflammation and plaque size. Adapted with permission (129). Copyright 2023, American Chemical Society. *p < 0.05, **p < 0.01 and ***p < 0.001.

Figure 7

Delivery of anti-cytokine antibodies using nanoparticles. (A) Biodegradable nanoparticle-antibody complexes exhibit effective neutralization of IL-6 and more prolonged anti-inflammatory action compared to free IL-6 antibodies. Adapted with permission (147). Copyright 2018, American Chemical Society. (B) Inflammation-targeting polyphenol-poloxamer nanoparticles were developed for oral administration to treat colitis, providing gastric protection for anti-TNF antibodies and ensuring targeted release in inflamed colon tissue. Adapted with permission (153). Copyright 2020, Ivyspring International Publisher. *p < 0.05, ***p < 0.001, and n.s. = not significant.

Figure 8

Macrophage membrane-coated nanoparticles (MΦ-NPs) for cytokine neutralization. (A) Motile green microalgae functionalized with MΦ-NPs are used for the active capture of proinflammatory cytokines within inflamed tissues in the gastrointestinal tract. Adapted with permission (171). Copyright 2024, American Association for the Advancement of Science. (B) MΦ-NPs are capable of neutralizing cytokines in human serum and synovial fluid samples from patients with inflammatory diseases. Adapted with permission (172). Copyright 2024, Wiley-VCH.

Figure 9

Neutrophil membrane-coated nanoparticles (Neu-NPs) for cytokine neutralization. (A) Neu-NPs neutralize proinflammatory cytokines in rheumatoid arthritis models. Adapted with permission (181). Copyright 2018, Nature Publishing Group. (B) Reactive oxygen species-responsive and oxygen-generating Neu-NPs enable the targeted treatment of refractory rheumatoid arthritis. Adapted with permission (182). Copyright 2024, Wiley-VCH.

Figure 10

Genetically engineered cell membrane-coated nanoparticles for cytokine neutralization. (A) Drug-loaded nanoparticles coated with genetically engineered umbilical vein endothelial cell membranes and modified with an inflammation-targeting ligand experience enhanced accumulation in inflamed joints for effective cytokine neutralization in rheumatoid arthritis. Adapted with permission (189). Copyright 2020, Elsevier. (B) Macrophages genetically modified to express proline-alanine-serine (PAS) peptide chains show extended in vivo retention time and enhanced efficacy in suppressing inflammatory cytokines in models of lipopolysaccharide-induced lung injury and endotoxemia. Adapted with permission (190). Copyright 2023, Wiley-VCH.