Innovative Dual mRNA-Lipid Nanoparticle Therapy Targeting CRHBP and CFHR3 for Enhanced Treatment of Hepatocellular Carcinoma

Int J Nanomedicine. 2024 Dec 7:19:13183-13199. doi: 10.2147/IJN.S498065. eCollection 2024.

Abstract

Purpose: Hepatocellular carcinoma (HCC) is a deadly disease requiring the identification of new therapeutic targets and strategies.

Methods: This study identified genes linked to HCC progression via differential analysis. Key genes were identified through univariate and multivariate Cox regression analysis. The biological effects of co-expressed CRHBP and CFHR3 were evaluated in vitro. mRNAs encoding CRHBP and CFHR3 were encapsulated in lipid nanoparticles (LNPs), with the addition of SP94 peptide on the LNPs surface to enhance targeting. The therapeutic efficacy of dual-mRNA LNPs was evaluated in HCC cells and mouse models.

Results: CRHBP and CFHR3 were closely associated with HCC progression. Low expression of CRHBP (P < 0.01, HR = 1.931 [1.174-3.175]) and CFHR3 (P < 0.05, HR = 1.755 [1.066-2.890]) was identified as a poor prognostic factor for HCC. The risk score model combining CRHBP and CFHR3 demonstrated superior predictive power (P < 0.001, HR = 2.935 [1.768-4.872]). Co-expression of CRHBP and CFHR3 significantly inhibited the malignant biological functions of HCC cells. Treatment with SP94 peptide-modified dual-mRNA LNPs markedly suppressed HCC tumor growth and exhibited excellent biocompatibility and safety.

Conclusion: Our study proposes a dual-targeted therapeutic strategy for HCC, which may represent a promising treatment approach.

Keywords: CFHR3; CRHBP; Lipid nanoparticles; mRNA.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / genetics
  • Cell Line, Tumor
  • Female
  • Humans
  • Liposomes / chemistry
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / genetics
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nanoparticles* / chemistry
  • RNA, Messenger* / genetics
  • RNA, Messenger* / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • RNA, Messenger
  • Lipid Nanoparticles
  • Liposomes

Grants and funding

This work was supported by the major science and technology R & D projects of Jiangxi Province (20213AAG01013), Natural Science Foundation of China (82472225,32071223,32100729, training plan for academic and technical leaders of major disciplines in Jiangxi Province (20213BCJ22015), Jiangxi Province Science and Technology Innovation Talent Project (jxsq2023201037), science and technology innovation base plan of Jiangxi Province (20212BCD42006), Natural Science Foundation of Jiangxi Province Youth Project (20242BAB20404), Youth Talent Research Training Foundation of the First Affiliated Hospital of Nanchang University (YFYPY2023103), Full time Talent Introduction and Research Start up Fund of the First Affiliated Hospital of Nanchang University(RSC-0020).