Co-delivery of hsa-miR-34a and 3-methyl adenine by a self-assembled cellulose-based nanocarrier for enhanced...

The simultaneous delivery of oligonucleotides and small molecules has garnered significant interest in cancer therapy. Hepatocellular carcinoma (HCC) treatment is hindered by limited efficacy and significant side effects. Homo sapiens microRNA-34a (hsa-miR-34a) has tumor suppressor properties and like small molecule 3-methyl adenine (3MA) can inhibit autophagy. Besides, 3MA has been shown to enhance anticancer effects in combination therapies. In the present study, a novel modified-cellulose-dialdehyde (MDAC) nanocarrier responsive to lysosomal pH was designed to co-load hsa-miR-34a polyplexes and 3MA and evaluate its antitumor efficacy against HCC. Polyplexes containing hsa-miR-34a and poly L lysine (PLL) with an optimal N/P ratio exhibited a zeta potential of +9.28. These polycations significantly modulated the surface charge of 3MA MDAC for optimal cell-membrane transport and dramatically increased their stability. The PLL-miR34a/3MA MDAC NPs had loading efficiency of around 99.7 % for miR-34a and 35 % for 3MA. Comply with pH dependency, PLL-miR34a polyplex/3MA MDAC NPs worked very efficiently on the inhibiting the expression of autophagy genes (p < 0.05), preventing the formation of autophagosomal vacuoles, reducing rate of cell survival, anti-migratory effects (>100 %), and triggering apoptosis (67.15 %) in HepG2. Our cellulose-based nanocarrier may demonstrate potential for enhancing therapeutic efficacy of combination therapies headed for future clinical translation in HCC.