Reverse-Engineered Lipid Nanoparticles Harness Protein Corona Formation for Cytokine Sequestration and Combination Immunomodulatory Therapy.

Cytokine storm drives the organ damage and mortality observed in sepsis, severe infection, and systemic inflammatory diseases. Despite decades of clinical effort, eliminating pathological cytokines from circulation remains an unmet medical need due to the risk of broad immunosuppression, significant toxicity, and off-target effects. Herein, guided by lipidomic insights from cytokine-sequestering lipid nanoparticles isolated from Lepidium meyenii Walp., we reverse-engineered triglyceride-ceramide lipid nanoparticles (TCNP) as a simplified synthetic nanoplatform that harnesses multimodal protein corona formation to broadly sequester pathological cytokines involved in systemic inflammatory disease. Rather than targeting a single cytokine axis, TCNPs were tuned to adsorb and neutralize multiple pro-inflammatory mediators through multimodal protein corona formation. TCNP were further engineered to encapsulate dexamethasone (Dex), conferring an additional layer of intracellular immunomodulation to complement extracellular cytokine scavenging. This dual function nanoplatform exhibited selective reduction of pro-inflammatory cytokines, including IL-6 and TNF-α while increasing regulatory IL-10 and suppressing NF-κΒ activation. In vivo, Dex-loaded TCNP attenuated systemic inflammation, preserved organ integrity, and significantly improved survival in a lethal lipopolysaccharide-induced endotoxemia rescue model. Collectively, these findings establish TCNP as a bioinspired nanotherapeutic platform that integrates extracellular cytokine sequestration with intracellular drug-mediated immunomodulation to overcome key limitations of conventional anti-inflammatory therapies.