The hepatocellular carcinoma (HCC) is a common and highly aggressive malignancy especially in China. Accumulating data have shown a critical role of long non-coding RNAs (lncRNAs) during cancer progression. However, the function of IncRNA TSLD8 remains elusive. By IncRNA profiling, we identify a novel IncRNA termed TSLD8 in HCC. TSLD8 expression is significantly lowered in HCC tissues and cell lines. TSLD8 facilitates migration and viability in SMMC-7721 and HepG2 cells. Furthermore, TSLD8 can interact with WWOX and protect WWOX from proteasome-mediated degradation. Using PuPGEA-based nanocomplex for gene delivery, we found that co-delivery of TSLD8 and WWOX may exhibit synergistic and additive effects to inhibit HCC progression. PuPGEA-based nanocomplex delivery does not substantially alter the blood chemistries (e.g. alkaline phosphatase, blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase) or initiate immune responses implying a safe strategy. Collectively, our current study has identified a novel tumor suppressive IncRNA TSLD8 which exerts its tumor suppressive function by stabilizing WWOX. Co-delivery of TSLD8 and WWOX via PuPGEA-based nanocomplexes might provide promising therapeutics for eradicating HCC. (C) 2019 Elsevier Inc. All rights reserved.