The success of gene therapy is highly dependent on the development of effective gene carriers that can overcome the systemic barriers to mediate gene transfection. Cationic helical polypeptides, affording potent membrane penetration activities, have demonstrated desired capabilities to efficiently mediate trans-membrane delivery of gene cargoes. In the current study, we reconfigured the topology of helical polypeptides with dendritic and brush structures, attempting to further potentiate their membrane activities while reduce the toxicities. We showed that the dendritic as well as brush helical polypeptides with “multivalent” structures afforded higher siRNA binding affinities than their linear analogue, and they provoked significantly enhanced membrane penetration properties via the “pore formation” mechanism. As such, the polypeptide-mediated silencing efficiency against macrophage migration inhibitory factor (MIF) and tumor necrosis factor-α (TNF-α) was augmented in macrophages. More importantly, we unraveled that such “multivalent” structures facilitated the penetration across the mucus layer on top of the lung epithelia, thus enhancing the delivery efficiency of siRNA into lung tissues and macrophages upon intratracheal delivery. As a result, the dendritic and brush helical polypeptides carrying MIF or TNF-α siRNA revealed potent gene silencing efficacy in the lung tissues upon intratracheal administration, and thus demonstrated desired anti-inflammatory effect against LPS-induced acute lung injury (ALI).

Engineering the topology of helical polypeptides toward anti-inflammation gene therapy

254th National Meeting (2017)

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