BTK-Inhibitor Loaded Polymeric Nanoparticles Alleviate Systemic Lupus Erythematosus by Targeting Elimination of Autoreactive BAFFRhigh B Cells

TL;DR

A new nanoparticle treatment targeting harmful B cells shows promise in reducing symptoms of lupus in mice without major side effects.

Contribution

A targeted nanoparticle system was developed to deliver BTK-inhibitors specifically to autoreactive B cells in lupus.

Findings

BTEL nanoparticles reduced anti-dsDNA autoantibodies and kidney damage in lupus mice.

The treatment decreased inflammatory cytokines and B cell activation without significant toxicity.

BAFFRhigh B cells were identified as key targets for BTK-inhibitor delivery in SLE.

Abstract

Systemic lupus erythematosus (SLE) is a chronic and refractory autoimmune disease characterized by multi-organ damage, for which reliably safe and effective treatment remains an unmet need. Autoantibodies, secreted by autoreactive B cells, deposition is the central pathogenesis of organ damage in SLE. Current studies reported B cell receptor and B cell activating factor (BAFF)-mediated signals regulate the activation and survival of B cells and production of autoantibodies. We showed that marginal zone B cells and CD11c+T-bet+ autoreactive B cells expressed higher levels of BAFF receptor and BTK in MRL/lpr mice. Here, a liposome-delivery system capable of targeting BAFFRhigh autoreactive B cells by conjugating anti-BAFFR antibody on the surface of the PEG-liposomes and loading BTK-inhibitor ibrutinib (BTEL) was rationally designed. Notably, the BTEL nanoparticles could inhibit the survival and activation of B cells, and systemic administration of BTEL could alleviate the development of the lupus mouse model by decreasing the production of anti-dsDNA autoantibodies, along with reduced secretion of inflammatory cytokines and kidney damage, and without apparent side effects. These findings suggest the potential of BTEL in targeting autoreactive B cells, blocking signaling pathways, and improving the efficacy of BTK inhibitors, providing a promising therapeutic approach for SLE, while also reducing toxicity.

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