Physicochemical design principles for B cell targeted acetalated dextran microparticles in antigen-specific tolerance...

Multiple sclerosis (MS) is an autoimmune disease currently being treated with broad immunosuppressive drugs. However, antigen-specific therapies offer a strategy to selectively reestablish self-tolerance within the autoreactive T cell compartment with fewer side effects. Polymeric microparticles are an effective platform for encapsulating disease-relevant antigens to achieve antigen-specific T cell tolerance via uptake by antigen-presenting cells (APCs). For this purpose, the most commonly targeted APCs are dendritic cells (DCs). However, B cells also present antigen and have demonstrated therapeutic efficacy in MS when targeted by depleting anti-CD20 antibodies. Microparticles comprised of the polymer acetalated dextran (Ace-DEX) bind to B cells more efficiently than other biomaterial systems and reside at the surface without internalization due to microparticle size. In this work, we systematically varied Ace-DEX parameters, including the fabrication method, molecular weight, hydrophobicity, and acetal exposure to understand the relationship between these properties and microparticle binding to B cells. These features strongly influenced B cell association, highlighting the sensitivity of immune recognition to polymer chemistry. The Ace-DEX MPs (AMPs) were evaluated in a preclinical MS model (experimental autoimmune encephalomyelitis (EAE)) using an adoptive transfer of ex vivo B cells surface decorated with MOG_35-55 loaded AMPs and achieved a significant decrease in the clinical score. This work demonstrates the role of polymer properties in B cell binding and outcomes as an antigen-specific therapeutic vaccine.