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RNAi-based therapeutics remains one of the most promising strategies for the effective cancer treatment due to its high target-specificity, precise mechanism of action, greater potency and reduced side effects. Although, tremendous progress and advances have been made in the past few years to develop nanotechnology-based efficient non-viral delivery systems, there are still many hurdles and challenges that must be conquered to achieve the target of clinically relevant formulation in terms of safety, specificity and efficacy.