Relaxin gene delivery mitigates liver metastasis and synergizes with check point therapy

Abstract

Activated hepatic stellate cell (aHSC)-mediated liver fibrosis is essential to the development of liver metastasis. Here, we discover intra-hepatic scale-up of relaxin (RLN, an anti-fibrotic peptide) in response to fibrosis along with the upregulation of its primary receptor (RXFP1) on aHSCs. The elevated expression of RLN serves as a natural regulator to deactivate aHSCs and resolve liver fibrosis. Therefore, we hypothesize this endogenous liver fibrosis repair mechanism can be leveraged for liver metastasis treatment via enforced RLN expression. To validate the therapeutic potential, we utilize aminoethyl anisamide-conjugated lipid-calcium-phosphate nanoparticles to deliver plasmid DNA encoding RLN. The nanoparticles preferentially target metastatic tumor cells and aHSCs within the metastatic lesion and convert them as an in situ RLN depot. Expressed RLN reverses the stromal microenvironment, which makes it unfavorable for established liver metastasis to grow. In colorectal, pancreatic, and breast cancer liver metastasis models, we confirm the RLN gene therapy results in significant inhibition of metastatic progression and prolongs survival. In addition, enforced RLN expression reactivates intra-metastasis immune milieu. The combination of the RLN gene therapy with PD-L1 blockade immunotherapy further produces a synergistic anti-metastatic efficacy. Collectively, the targeted RLN gene therapy represents a highly efficient, safe, and versatile anti-metastatic modality, and is promising for clinical translation.

Lipid nanoparticle technology for therapeutic gene regulation in the liver

“…As only limited therapies are available for liver cancer, this methodology could well be used towards identifying effective and novel treatments for liver cancer. Although lipid calcium phosphate nanoparticles (LCPs) are beyond the scope of this review, in the context of liver cancer, it is relevant to note the work by Leaf Huang and colleagues demonstrating that LCP-based DNA delivery enables mitigation of liver metastasis [176][177][178].…”

Lipid Nanoparticles for Cell-Specific <i>in Vivo</i> Targeted Delivery of Nucleic Acids

“…84) Narmada et al used vitamin A-coupled liposomes to deliver pDNA encoding the hepatocyte growth factor gene to activated hepatic stellate cells (aHSCs) for the amelioration of liver fibrosis. 85) Huang's group designed LCP NPs that were surface modified with aminoethyl anisamide to target the sigma-1 receptor in aHSCs and deliver pDNA expressing the antifibrotic peptide relaxin. 86) 3.4.…”

The Two Faces of Relaxin in Cancer: Antitumor or Protumor?

“…Nakamura et al recently investigated the role of intestinal microbiota of the recipient on development of IRI and early liver allograft dysfunction. (2) In this translational study, the investigators first used a mouse liver transplant model with a prolonged cold storage of liver allografts to mimic marginal human liver grafts. In this model, mice that were pretreated with oral amoxicillin for 10 days prior to transplant had less liver tissue damage, both histologically and biochemically.…”

“…(1) However, what cells constitute this favorable metastatic niche and whether they can be therapeutically targeted remain open questions.In a recent issue of Nature Communications, Hu et al generated an in situ relaxin (RLN) depot by employing lipid-calcium phosphate (LCP) nanoparticles to target delivery of RLN plasmid (pRLN) to hepatic metastatic lesions. (2) The nanoparticles preferentially targeted hepatic stellate cells (HSCs). Why target HSCs?…”