Smart nanoparticles for drug, gene and nitric oxide delivery

   Intelligent nanomedicine is one of the most promising strategies for the delivery of therapeutics with reduced side effects and enhanced efficacy. To date, we have explored the potential of various stimuli-responsive nanomedicine, including inorganic nanoparticles and biopolymers, for the delivery of a wide range of therapeutic agents such as chemotherapeutics, genes, and the gas molecule. Supramolecular self-assembled nanostructures have attracted a vast amount of attention as an enticing material for intelligent nanomedicine in a complex biological system. For preparing self-assembled nanostructures, we judiciously conjugated a self-assembly pair into different polymer backbones, achieving highly stable nanostructure formation. Various self-assembled pairs, including a host-guest interaction of paclitaxel (PTX)/cyclodextrin (CD) and base-specific interactions between the sense and antisense strands of siRNA, were chemically conjugated on each polymer backbone. Another strategy is to modulate the size and structure of the assembled structure using the sequence-specific hybridization and dehybridization of pH-sensitive functional DNA known as the i-motif. According to pH changes, the structure of functional DNA was transformed dynamically, leading to a release of the cargo, thus achieving the specific delivery of siRNA or an anticancer drug, doxorubicin (DOX).In this presentation, we reveal the design, construction, and operation of a functional DNA-decorated dynamic gold (Au) nanomachine as a therapeutic agent for triple combinatorial anti-cancer therapy. Taking advantage of the intrinsic optical properties of Au nanoparticles, which depend on their size, a cytosine rich i-motif sequence was employed for intracellular pH-sensitive duplex dissociation and subsequent aggregation of the DNA-Au nanomachine, enabling anti-cancer drug release and photothermal ablation upon irradiation with infrared light. Moreover, another functional DNA sequence, a G-quadruplex, was exploited for the stable loading and intracellular delivery of a photosensitizer to achieve effective photodynamic therapy under red light illumination. The G-quadruplex-assisted enhanced reactive oxygen species generation, pH-responsive dynamic aggregation behavior, consequent drug release, and the photothermal effect were investigated. Furthermore, the combinatorial chemo, photodynamic, and photothermal therapeutic effects of the functional DNA-decorated Au nanomachines were evaluated in vitro and in vivo using a triple negative breast cancer model. We also report novel platform of nitric oxide (NO) delivery using polydopamine and light-responsive NO-releasing nanoparticles. For the stimuli-sensitive No delivery system, we designed a light-responsive gatekeeper for smart NO delivery. The gatekeeper is composed of a pH-jump reagent as an intermediary of stimulus and a calcium phosphate (CaP) coating as a shielding layer for NO release. The light irradiation and subsequent acid generation are used as triggers for uncapping the gatekeeper and releasing NO. The acids generated from a light-activated pH-jump agent loaded in the mesoporous nanoparticles accelerated the degradation of the CaP-coating layers on the nanoparticles, facilitating the light-responsive NO release from diazeniumdiolate by exposing an NO donor to physiological conditions. Using the combination of the pH-jump reagent and CaP coating, we successfully developed a light-responsive gatekeeper system for spatio-temporal controlled NO delivery.