Versatile Nanodelivery Platform to Maximize siRNA Combination Therapy.

The unsatisfactory outcomes of typical multiple cytotoxic chemotherapeutic combination therapies used to treat patients have fostered a need for new unconventional combinations of therapeutic agents. Among the candidates, siRNA has been widely discussed and tested. However, the right time right place codelivery of siRNA with other types of active ingredients is challenging because of the possible differences among their physiochemical and pharmacodynamics properties. To accomplish a synergistic cytotoxic effect, a nanoassembly is thus designed to codeliver siRNA with other therapeutic agents. A siRNA, targeting prosurvival gene for the p75 neurotrophin receptor, and an organelle-fusing peptide, targeting mitochondria, are layered onto a nanotemplate by charge-charge interaction, followed by a layer of CD44 targeting ligand. The formulated triple-functional nanomedicine is efficiently internalized by the CD44 expressing triple-negative breast cancer cells. The encapsulated siRNA and the pro-apoptotic peptide are released inside cells, silencing the intended prosurvival gene, and inducing apoptosis by fusing the mitochondrial membrane, respectively. A synergistic effect is achieved by this three-agent combination. The design of the developed multifunctional nanomedicine can be generalized to deliver other siRNA and drugs for a maximum therapeutic combination with minimal off-targeting effects.