Subcellular two-pronged targeting therapeutics: disrupting mitochondria-endoplasmic reticulum communication in inflammatory disorders

Researchers have made significant efforts to develop mitochondria or endoplasmic reticulum (ER)-targeting strategies to regulate cellular signaling cascades in inflammatory diseases. Although ER and mitochondria function relatively independently, these organelles can form extensive physical interactions, known as mitochondria-associated ER membranes (MAMs). Emerging evidence suggests that the development of inflammatory diseases depends largely on the pathological crosstalk between mitochondria and ER through MAMs, whereby ER stress and mitochondrial dysfunction collectively activate inflammatory signaling. Due to the presence of MAMs, single-organelle (ER or mitochondria)-specific therapies may not adequately suppress inflammatory signaling activation, highlighting the need for two-pronged strategies to thoroughly interfere with the pathological crosstalk between ER and mitochondria. This review highlights how the interaction between mitochondria and ER contributes to the progression of inflammatory diseases, and systematically summarizes the current advances in delivery strategies for ER and mitochondria targeting. Furthermore, we emphasize the therapeutic potential of simultaneously regulating mitochondrial and ER function to achieve precise control of inflammatory disorders. Our review aims to establish a framework for two-pronged targeting strategies that can restore ER and mitochondrial homeostasis, thereby facilitating the treatment of inflammatory diseases. STATEMENT OF SIGNIFICANCE: Due to the extensively formed mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) under inflammatory conditions, previous studies focusing on modulating the dysfunction of either mitochondria or ER have demonstrated limited efficacy in inflammatory disorders. MAM-mediated pathological inter-organelles crosstalk can drive the vicious cycle between mitochondria dysfunction and ER stress in inflammatory diseases, underscoring the need for two-pronged approaches that precisely disrupting mitochondria-ER communication. This review highlighted the key role of MAMs in inflammation and summarized recent advances in ER/mitochondria targeted delivery strategies. Furthermore, we underscored the potential therapeutic targets within MAMs for inflammatory intervention, and discussed therapeutic potential of two-pronged approaches in restoring organelle homeostasis and mitigating inflammatory diseases.