A Review of pH-Responsive Organic-Inorganic Hybrid Nanoparticles for RNAi-Based Therapeutics

RNA interference (RNAi) shows great potential in the treatment of varying cancer and genetic disorders. The lack of safe and effective delivery methods is an ongoing challenge to realize the full potential of RNAi-based therapeutics. pH-responsive hybrid nanoparticle is a promising non-virus platform for small interfering RNA (siRNA) delivery with unique properties including the robust response to the acidic microenvironment and the capability of theranostic and combined therapeutics. The mechanism of RNAi and the delivery barriers for RNAi-based therapeutics are first discussed. Then, the general patterns of pH-response and the typical construction of hybrid nanoparticles are demonstrated. The recent advances in pH-responsive organic-inorganic hybrid nanoparticles for siRNA delivery are highlighted, in particular, how pH-response of ionizable groups, acid-labile bonds, and decomposition of inorganic components affect the physicochemical properties of hybrid nanoparticles and benefit the cellular uptake and intracellular trafficking of siRNA payloads are discussed. At last, the remaining problems and the prospects for pH-responsive hybrid nanoparticles for siRNA delivery are analyzed.