Controlled Dimerization of Cellular Nanodiscs via Click Chemistry to Enhance Immune Compatibility.

Cellular nanodiscs (CNDs), assembled from cell membrane fragments and stabilized with scaffold molecules, have emerged as a promising biomimetic platform for drug delivery, countermeasures, and vaccination. However, the exposure of inner membrane components in the current CND constructs, such as phosphatidylserine (PS) can trigger immune recognition and rapid clearance, thereby limiting their therapeutic efficacy. To address this issue, here we report on a unique approach to dimerizing CNDs in a precisely controlled, back-to-back manner by covalently linking two monomeric CNDs via click chemistry, aiming to shield the immunogenic inner membrane components. Compared with monomeric CNDs, the resulting dimeric CNDs showed reduced PS exposure, decreased macrophage uptake, and prolonged circulation in vivo. In mouse models of acute lung injury and systemic inflammation, dimeric CNDs achieved superior cytokine suppression and favorable biodistribution with minimal short-term toxicity. These findings demonstrate that CND dimerization can effectively enhance immune compatibility and greatly improve in vivo performance, advancing the application potential of cell membrane-derived CND technology.