A modular design of two-pronged sub-organelle targeting strategy disrupting mitochondria-endoplasmic reticulum crosstalk for mitigating rheumatoid arthritis

The pathological crosstalk between endoplasmic reticulum (ER) stress and mitochondria (MT) dysfunction aggravates rheumatoid arthritis (RA) process by promoting the abnormal formation of mitochondria-associated ER membranes (MAMs). Current single organelle-specific therapies are insufficient to halt MAMs-mediated pathological inter-organelle communication and thereby showed limited efficacy in suppressing RA. A two-pronged dual organelles regulatory strategy that concurrently inhibit ER stress and MT dysfunction, thereby suppressing the aberrant MAMs formation will be promising to achieve prolonged RA remission. Due to the multiple delivery barriers from tissue to sub-organelle level, conventional approaches involve decorating nanocarriers with multiple functional groups. However, this typically leads to increased structural complexity and unpredictable in vivo performance. Here, we adopted a minimalist modular design strategy. By fine-tuning the density and ratio of dual organelles-targeted modules, we optimized the physicochemical properties of the Res@DPGT nanoplatform for maximal sub-organelle drug delivery. The optimal two-pronged nanoplatform Res@DPGT achieve a hierarchical targeting process from the tissue level to sub-organelle level, ultimately delivering therapeutic resveratrol (Res) to ER and MT. In inflammatory cells, Res@DPGT significantly suppress ER stress and MT dysfunction by disrupting MAMs formation, eliciting potent anti-inflammatory efficacy. In arthritic rats, intravenously administrated Res@DPGT show enhanced internalization by circulating monocytes and leverage the inflammatory tropism of circulating monocytes to achieve preferential distribution and prolonged retention in inflamed joints. Ultimately, Res@DPGT remarkedly alleviate RA by disrupting the MAMs-mediated pathological ER-MT coupling.