Degradable MMP9-responsive high-density lipoprotein nanoparticles enable efficient siRNA-PGRN and quercetin delivery to remodel the fibrotic microenvironment and attenuate renal fibrosis.

Renal fibrosis is the final common pathway of chronic kidney disease and remains a challenge due to the complex fibrotic and inflammatory microenvironment. This study aimed to develop an enzyme-responsive, fibrosis-targeted nanotherapeutic system capable of simultaneously delivering siRNA against progranulin (siPGRN) and quercetin (QT) to remodel the fibrotic microenvironment and effectively attenuate renal fibrosis. The TIMP-HDL-Nano@siPGRN&QT nanoparticles prepared in this study exhibit uniform nanoscale size (~ 100 nm), high encapsulation efficiency, excellent stability, and favorable biocompatibility. The MMP9-responsive modification significantly enhanced renal accumulation and fibrotic lesion targeting in vivo. Treatment with TIMP-HDL-Nano@siPGRN&QT markedly alleviated UUO-induced renal injury, apoptosis, and fibrosis, outperforming free drug. Transcriptomic and mechanistic analyses revealed that the therapeutic effects were mediated through disruption of the PGRN-PPARα interaction, restoration of PPARα signaling, and subsequent inhibition of NF-κB-driven inflammatory pathways. Furthermore, the nanoparticles suppressed pro-inflammatory M1 macrophage polarization and promoted M2 polarization in a PPARα-dependent manner. This study demonstrates that TIMP-HDL-Nano@siPGRN&QT enables efficient, targeted co-delivery of siRNA and small-molecule therapeutics to fibrotic kidneys. By remodeling the fibrotic immune microenvironment through the PGRN-PPARα-NF-κB axis, this nanoplatform provides a potent and mechanistically defined strategy for the treatment of renal fibrosis and offers translational potential for other inflammation-driven fibrotic diseases.