SLPI-Loaded Liposomes Targeting Kupffer Cells Modulate Macrophage Polarization and Mitigate Radiation-Induced Liver Damage.

Kupffer cells (KCs) make up the predominant population of resident innate immune cells in the liver, serving as key immune sentinels that maintain local immune surveillance and immunoregulatory homeostasis. However, their functional involvement and phenotypic dynamics during radiation-induced liver damage (RILD) remain insufficiently explored. Therefore, we established a mouse model of RILD and, through systematic single-cell-level profiling of hepatic immune cell populations, found that KCs play a critical role in hepatic immune responses and undergo a pronounced radiation-induced shift toward a pro-inflammatory M1 phenotype. Further KC depletion/reconstitution, molecular assays, and coculture experiments consistently demonstrated that M1-polarized KCs exacerbate liver damage, with secretory leukocyte protease inhibitor (SLPI) being identified as a key molecular mediator driving this polarization and its pathogenic effects. To further substantiate these findings, we designed a liposome-based delivery strategy to selectively inhibit SLPI in KCs, which effectively suppressed M1 polarization and alleviated radiation-induced liver damage, underscoring the therapeutic relevance and translational potential of this approach in RILD. Overall, these findings demonstrate that radiation drives KCs toward an SLPI-dependent pro-inflammatory M1 state, thereby exacerbating liver injury. Moreover, targeted liposomal suppression of SLPI effectively reverses this polarization and protects against RILD, highlighting SLPI-modulated KC reprogramming as a promising therapeutic approach.