Engineering an abiotic antibody mimic: Structural and molecular mechanisms for targeting, neutralizing, and...

Abiotic antibody mimics offer promising alternatives to antibodies in diagnostics and therapeutics. Herein, we engineer an abiotic antibody mimic, a hydrogel polymer nanoparticle (NP), for targeting the SARS-CoV-2 spike antigen and, based on this, construct a core-shell nanoprobe by in situ polymerization on AuNPs for precise antigen/pseudovirus recognition and point-of-care testing. The optimal antibody mimic, N-acryloyl-_L-tryptophan (ATrp)-NP7, is selected from rationally designed polymer NP libraries derived from aromatic amino acid monomers (ATrp, ATyr, and APhe). Structurally, a synergistic steric effect arising from the chemical identity and spatial arrangement of anionic carboxyl and aromatic indolyl groups governs spike RBD binding. Mechanistically, key epitopes and residues involved in ATrp-NP7 binding coincide with ACE2-binding sites, enabling competitive inhibition of spike RBD-ACE2 interactions with efficacy comparable to that of antibodies. By integrating the detection probe Au@ATrp-NP7, the probe capture unit MLys-NP6, and/or the antigen recognition element ATrp-NP7, we develop entirely biomolecule-free lateral flow immunoassays for SARS-CoV-2 spike antigens and pseudoviruses. This study highlights abiotic antibody mimics as versatile tools for antigen targeting, neutralizing, visualizing, and point-of-care testing. It also provides a novel paradigm for developing robust, mutation-tolerant abiotic synthetic antibodies to address potential future pandemics caused by emerging pathogens.