Multivalent Protein Nanorings for Broad and Potent SARS-CoV-2 Neutralization
Behbahanipour, Molood (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Goldin, Carla (Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina))
Prato, Cecilia Arahi (Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas (Argentina))
Paletta, Ana Luz (Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas (Argentina))
Bárcenas, Oriol (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Navarro, Susanna (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Pujols, Jordi (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Murgida, Daniel H. (Universidad de Buenos Aires. Departamento de Química Inorgánica, Analítica y Química Física)
Tribulatti, María Virginia (Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas (Argentina))
Esperante, Sebastián (Consejo Nacional de Investigaciones Científicas y Técnicas)
Alvarez-Paggi, Damian (Consejo Nacional de Investigaciones Científicas y Técnicas)
Ventura, Salvador (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))

Date:	2025
Abstract:	The 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(IC) 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, 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.
Grants:	Agencia Estatal de Investigación PID2022-137963OB-I00 Ministerio de Ciencia e Innovación FPU22/03656 Ministerio de Ciencia e Innovación PRE2020-092634
Note:	Altres ajuts: acords transformatius de la UAB
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Minibinders ; Protein scaffold ; SARS-CoV-2 ; Therapeutic ; Viral neutralization
Published in:	Advanced Healthcare Materials, (October 2025) , art. e03487, ISSN 2192-2659

DOI: 10.1002/adhm.202503487

16 p, 2.6 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Parc Taulí Research and Innovation Institute (I3PT
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
Articles > Published articles