2. Academic Validation
  3. An oral nanocombinatorial agent exhibits pleiotropic improvement in diabetic nephropathy via modulation of the SCAP/SREBPs pathway

An oral nanocombinatorial agent exhibits pleiotropic improvement in diabetic nephropathy via modulation of the SCAP/SREBPs pathway

  • J Nanobiotechnology. 2026 Mar 22;24(1):405. doi: 10.1186/s12951-026-04301-9.
Yu Su # 1,  Haobo Wen # 2,  Ke Hu # 2,  Cuiping Wen 2,  Ping Wang 2,  Lulu Zhao 2,  Gang Zou 3,  Wei Jiang 1,  Yaxi Chen 4 5,  Yunfei Zhao 6,  Qiu Li 7
Affiliations

Affiliations

  • 1 Department of Nephrology, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Children's Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China.
  • 2 Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, , the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, P. R. China.
  • 3 College of Pharmacy, Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, Chongqing Medical University, Chongqing, 400016, P. R. China.
  • 4 Department of Nephrology, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Children's Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China. [email protected].
  • 5 Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, , the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, P. R. China. [email protected].
  • 6 Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, , the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, P. R. China. [email protected].
  • 7 Department of Nephrology, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Children's Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China. [email protected].
  • # Contributed equally.
PMID: 41866523 DOI: 10.1186/s12951-026-04301-9
Abstract

The multifaceted pathogenesis and multi-cellular involvement of diabetic nephropathy (DN) stand in stark contrast to the inadequacy of conventional single-target therapeutic strategies. This disparity underscores the urgent need for novel drugs with comprehensive targeting capabilities. Herein, the SREBP cleavage-activating protein/sterol regulatory element-binding proteins (SCAP/SREBPs) pathway was identified as a central driver in DN, where its activation in key renal parenchymal cells promotes lipid metabolic disorders and inflammation, thereby exacerbating renal injury. Guided by this discovery, we screened a 245-member nanoparticle library comprising SCAP inhibitors self-assembled with chitosan, and identified chitosan-lycorine nanoparticles (CLNPs) as the optimal candidate. Owing to its efficient intestinal absorption and significant accumulation in mesangial and proximal tubular epithelial cells, oral CLNPs strongly alleviated renal injury in a murine model of DN by counteracting lipid accumulation and inflammation, consistent with SCAP/SREBPs pathway inhibition. Critically, CLNPs prevented hepatotoxicity from free lycorine, which reduced mortality and enabled safer prolonged therapy. Together, our findings demonstrate the viability of CLNPs for DN, thereby offering a generalizable strategy for combating complex diseases through a single combinatorial agent that counters multiple co-existing pathological injuries.

Keywords

Diabetic nephropathy; Inflammation; Lipid metabolic disorders; Lycorine; Oral delivery; SCAP/SREBPs.

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