A Dual‐Membrane Biomimetic Nanoplatform Enables Triple‐Modal Therapy Against SARS‐CoV‐2 Through Viral Decoy, Inflammation Neutralizing, and Intracellular RNAi

The persistent evolution of SARS-CoV-2 and the concomitant risk of life-threatening hyperinflammation, such as cytokine storm syndrome, underscore the urgent need for therapeutic strategies that simultaneously target viral replication and dysregulated host immunity. Herein, we describe a dual-membrane biomimetic nanoplatform, designated [A&T]MLN, comprising siRNA-loaded lipid nanoparticles with a hybrid membrane derived from ACE2-overexpressing HEK293T cells and THP-1 macrophages. This design integrates a high-density viral decoy based on ACE2 with the inherent immunomodulatory capacity of macrophage membranes. [A&T]MLN demonstrates broad-spectrum and potent neutralization of diverse SARS-CoV-2 variants by competitively blocking viral entry, while actively scavenging key inflammatory cytokines (including IL-6, IL-1β, and TNF-α) via membrane-displayed receptors. In a murine model of acute lung injury that recapitulates COVID-19 immunopathology, [A&T]MLN treatment significantly attenuated pulmonary inflammation and tissue damage. Additionally, the platform enabled efficient cytosolic delivery of siRNA, establishing a third modality for intracellular suppression of viral gene expression. Collectively, [A&T]MLN represents a complementary triple-modal therapy that simultaneously addresses viral entry, intracellular replication, and hyperinflammation (the core interconnected pathologies of severe COVID-19), offering a versatile and adaptive strategy against evolving SARS-CoV-2 variants and related inflammatory syndromes.