Development of a hybrid biomaterial system for immunotherapy of rheumatoid arthritis

The National Institute of Allergy and Infectious Diseases awarded the University of Florida $607,599 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop a hybrid biomaterial immunotherapy system for rheumatoid arthritis.

The funded work centers on engineering and testing REGVAK, a novel hybrid polymeric microparticle–lipid nanoparticle system designed to address the root cause of rheumatoid arthritis by targeting dendritic cell activation of autoreactive T lymphocytes. The system combines DC-targeting microparticles that deliver antigens (denatured collagen and citrullinated fibrinogen) and a tolerizing drug (vitamin D3) with lipid nanoparticles containing mRNA for proteins that drive DC recruitment and tolerogenicity. The Lewis Lab at the University of Florida will engineer REGVAK to attenuate disease progression in an aggressive murine rheumatoid arthritis model and investigate immune modulation following treatment. Preliminary studies with REGVAK's predecessor, REGVAC, demonstrated significant arthritis remission in collagen-induced and citrullinated fibrinogen-induced arthritic mouse models.

Performance occurs in Gainesville, Florida. The award runs through August 31, 2027. This is a Project Grant, the standard assistance type for investigator-initiated research under the NIAID portfolio.

Abstract

Rheumatoid arthritis (RA) is a chronic, systemic, auto-inflammatory disease that affects approximately 1% of adults worldwide, and commonly results in joint destruction and significant impairment in the quality of life. The underlying cause of RA is dendritic cell (DC) activation of antigen-specific t cell subsets in the joints, which drive inflammatory responses to the synovial membrane that are typically characterized by hyperplasia, increased vascularity, inflammatory cell infiltration and over production of pro-inflammatory cytokines (particularly IL-1, IL- 6 and TNF-α) by monocytes, macrophages and synovial fibroblasts. Current clinical strategies do not address the root cause of RA - stimulation and activation of autoreactive t lymphocytes by DCS. The lewis lab at UF is developing a novel hybrid polymeric microparticle (MP) - lipid nanoparticle (LNP) system for immunotherapy of RA. More specifically, this system (called regvak) is composed of i.) DC-targeting, phagocytosable MP delivering antigen (denatured [collagen/ citrullinated fibrinogen]) and tolerizing drug (vitamin D3) to intracellular receptors and, II.) lnps containing mrna for proteins that drive DC recruitment and tolerogenicity - GM-CSF + TGF-Β1, respectively. Moreover, in preliminary studies, administration of the predecessor of this system, regvac, resulted in significant remission of arthritis in a collagen-induced/ citrullinated fibrinogen-induced arthritic mouse model (see research strategy). Our long-term goal is to develop an antigen-specific immune-modulatory platform for rheumatoid arthritis (and autoimmune disease) therapy. The overall objective of this R01 proposal is to engineer regvak to attenuate RA progression in an aggressive, murine RA model, and investigate the extent of immune modulation following 'anti-vaccination'. Our central hypothesis is that regvak will induce autoantigen-specific tolerance by targeted delivery of model-relevant autoantigen and tolerance-inducing factors to immune cells, especially DCS, thereby generating AAG-specific tdcs that will retrain downstream adaptive responses and promote the remission of RA. This novel therapeutic has promise to correct aberrant autoimmune responses, whilst circumventing problems associated with DC- based cellular therapy such as DC phenotypic stability and survivability, and autoantigen plurality. Our hypothesis will be tested by pursuing three specific aims: 1) engineering regvak for optimal and effective tolerogenicity; 2) assessing in vitro and in vivo mechanics of regvak; and 3) evaluate efficacy and investigate mechanisms of immune tolerance using well-defined antigen-specific mouse models. The approach is innovative, in the applicant's opinion, because IT departs from the status QUO by generating specific tolerance- inducing cellular mediators in vivo with a simple subcutaneous injection. Ultimately, the research and development of this system has the potential to significantly stem the growing epidemic of autoimmunity in the US.