RLP-1,3 for COVID-19

AbstractThe ongoing threat of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and the limitations of conventional antibody‐based therapeutics (ABTs) underscore the need for scalable and customizable antiviral platforms. A modular, protein‐only nanoscaffold based on recombinant ring‐like particles (RLPs) derived from a viral nucleoprotein (NP), engineered is presented to display high‐affinity, de novo‐designed minibinders (LCB1 and LCB3) targeting SARS‐CoV‐2 Spike (S)protein. These binders are site‐specifically fused to either the N‐ or C‐termini, or both ends of NP to ensure functional orientation and dense, multivalent display. The resulting constructs self‐assemble into stable, biocompatible, and homogeneous nanoparticles that potently inhibit S–angiotensin‐converting enzyme 2 receptor (ACE2r) interactions, neutralizing both pseudotyped viral‐like particles and authentic SARS‐CoV‐2, including Omicron BA.5. The dual‐display nanoparticle (RLP‐1,3), presenting 10 LCB1 and 10 LCB3 domains, exhibit synergistic binding activity, with fM Half Maximal Inhibitory Concentration(IC50) values, outperforming benchmark monoclonal antibodies and clinically approved hyperimmune therapies. Additionally, RLP‐1,3 is adapted for diagnostics in an ELISA platform, achieving a Spike protein detection limit of 9 ng mL−1, surpassing commercial assays. This work demonstrates how the convergence of AI‐guided binder design and structure‐based nanoscaffolding enables next‐generation multifunctional bio‐nanomaterials. The RLP‐minibinder system offers a generalizable, scalable, and cost‐efficient plug‐and‐(dis)play solution with integrated therapeutic and diagnostic capabilities, positioning it as a flexible alternative to ABTs for pandemic preparedness.