Engineered Spirulina platensis for treating rheumatoid arthritis and restoring bone homeostasis.

Rheumatoid arthritis (RA) is characterized by massive intra-articular infiltration of pro-inflammatory macrophages, leading to articular immune dysfunction, severe synovitis, and ultimately joint erosion. Comprehensive remodeling of articular immune homeostasis and bone homeostasis is essential for alleviating RA. Here we report on Spirulina platensis (SP), a natural microorganism commercially farmed worldwide as a food, as an efficient regulator of both synovial inflammation and osteoclast differentiation in male RA mouse models. SP reduces excessive reactive oxygen species and downregulates pro-inflammatory cytokines in synovial macrophages. Moreover, SP reprograms pro-inflammatory M1-like macrophages to anti-inflammatory M2-like phenotype, suppressing synovitis and remodeling redox balance. Notably, SP inhibits osteoclast activation effectively and blocks the progression of bone erosion. SP is then engineered with macrophage membranes (SP@M) to enable immune evasion and RA-targeting in vivo. SP@M increases LC3-mediated autophagy as well as strengthens ubiquitin-mediated proteasomal degradation toward KEAP1, which promotes the expression and nuclear translocation of NRF2. The NRF2 further activates antioxidant enzymes to terminate macrophages-initiated pathological cascades and reestablish intra-articular immune homeostasis, conferring a bone recovery and chondroprotective effect in collagen-induced arthritis mouse models. This work shows the therapeutic activity of FDA-approved functional food of SP in suppressing synovial inflammation and osteoclast differentiation, offering an off-the-shelf strategy for RA treatment.