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The nanoplexes were obtained through nanoprecipitation and were characterized by a mean diameter of ~160\u2009nm, a good size distribution and a positive surface charge. The structure of the nanoparticles allowed a high level of entrapment efficiency of the miR-34a and provided protection of the genetic material from the effects of RNase. A high degree of transfection efficiency of the nanoplexes and a significant <jats:italic>in vitro<\/jats:italic> antitumor effect against multiple myeloma cells was demonstrated. The therapeutic properties of the nanoplexes were evaluated <jats:italic>in vivo<\/jats:italic> against human multiple myeloma xenografts in NOD-SCID mice. The systemic injection of miR-34a mimic-loaded nanoparticles significantly inhibited tumor growth and translated into improved survival of the laboratory mice. RT-PCR analysis carried out on retrieved tumors demonstrated the presence of a high concentration of miR-34a mimics. 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