Background: Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a novel tumor suppressor. However, whether LHPP is effective to melanoma has not been investigated. Gene therapy provides a new strategy for the treatment of melanoma. Currently, it suffers from the lack of safe and effective gene delivery systems. 
Methods: A CRGDKGPDC peptide (iRGD) modified hybrid monomethoxy poly(ethylene glycol)-poly(D,L-lactide) nanoparticle (iDPP) was prepared and complexed with a LHPP  plasmid, forming an iDPP/LHPP  nanocomplex. The iDPP/LHPP  nanocomplex was characterized by particle size distribution, zeta potential, morphology, cytotoxicity, and transfection efficiency. The antitumor efficacy of the nanocomplex against melanoma was studied both in vitro and in vivo. Further, the potential epigenetic changes in melanoma induced by iDPP/LHPP  nanocomplex were evaluated.
Results: The iDPP/LHPP  nanocomplex showed high transfection efficiency and low toxicity. Moreover, the nanocomplex displayed a neutral charge that can meet the requirement of intravenous injection for targeted gene therapy. In vitro and in vivo experiments indicated that the iDPP/LHPP  nanocomplex significantly inhibited the melanoma growth without causing notable adverse effects. We also found that LHPP  played an important role in epigenetics. It regulated the expression of genes related to the proliferation and apoptosis chiefly at the level of transcription.
Conclusion: This work demonstrates that the iDPP nanoparticle-delivered LHPP  gene has a potential application in melanoma therapy through regulation of the genes associated with epigenetics.
Keywords: melanoma, LHPP, nanoparticle, gene therapy, epigenetics