MnO₂ and roflumilast-loaded probiotic membrane vesicles mitigate experimental colitis by synergistically augmenting cAMP in macrophage

Ulcerative colitis (UC) is one chronic and relapsing inflammatory bowel disease. Macrophage has been reputed as one trigger for UC. Recently, phosphodiesterase 4 (PDE4) inhibitors, for instance roflumilast, have been regarded as one latent approach to modulating macrophage in UC treatment. Roflumilast can decelerate cyclic adenosine monophosphate (cAMP) degradation, which impedes TNF-α synthesis in macrophage. However, roflumilast is devoid of macrophage-target and consequently causes some unavoidable adverse reactions, which restrict the utilization in UC.

Membrane vesicles (MVs) from probiotic Escherichia coli Nissle 1917 (EcN 1917) served as a drug delivery platform for targeting macrophage. As model drugs, roflumilast and MnO₂ were encapsulated in MVs (Rof&MnO₂@MVs). Roflumilast inhibited cAMP degradation via PDE4 deactivation and MnO₂ boosted cAMP generation by activating adenylate cyclase (AC). Compared with roflumilast, co-delivery of roflumilast and MnO₂ apparently produced more cAMP and less TNF-α in macrophage. Besides, Rof&MnO₂@MVs could ameliorate colitis in mouse model and regulate gut microbe such as mitigating pathogenic Escherichia–Shigella and elevating probiotic Akkermansia.

A probiotic-based nanoparticle was prepared for precise codelivery of roflumilast and MnO₂ into macrophage. This biomimetic nanoparticle could synergistically modulate cAMP in macrophage and ameliorate experimental colitis.