Stimuli-Responsive Porous Nanomaterials for Controlled Drug Delivery and Gene Therapy

Tutkimustuotos: VäitöskirjatyypitTohtorinväitöskirjaArtikkelikokoelma


Stimuli-responsive drug delivery systems have become increasingly fascinating and vital in nanomedicine because they can change the drugs pharmacokinetics, significantly improve the drugs utilization efficiency, provide on-demand local drug delivery, and reduce toxic side effects. As a typical representative, porous nanomaterials have unique physicochemical properties, such as rich pore structure, low density, high surface area, and tunable porous size. They show great promise not only in industrial catalysis, gas adsorption, linear optics, and electromagnetic materials, but also in stimuliresponsive delivery system for the diagnosis and treatment of diseases. This thesis mainly focuses on some important scientific issues such as seeking new release and targeting mechanisms, broadening their biomedical applications, developing multifunctional drug delivery systems, exploring biomimetic encapsulation strategies, and further improving the loading diversity of nanocarriers. Here, we have designed different drug/biomolecule delivery systems based on porous nanomaterials, which are listed as follows:

First, mesoporous silica nanoparticle (MSNs)-based drug delivery system with in vivo endothelial targeting was prepared for the inhibition of antibodymediated rejection after allograft kidney transplantation. The photothermal sensitive copper sulphide (CuS) nanoparticles were encapsulated in biocompatible MSNs, followed by multi-step surface engineering to form the anti-inflammatory drug-loaded theragnostic nanoparticles. Non-invasive targeting imaging, and near-infrared (NIR) triggered photothermal responsive drug release investigations demonstrated this system can reduce systemic inflammation, downregulate innate immune responses and promote recovery of the injured endothelium. Intracellular delivery of CRISPR/Cas9 plasmids via MSNs was subsequently explored for homology-directed repair through gene editing. By microfluidic-assisted electrostatic nanoprecipitation, polymer was coated onto plasmid-loaded MSNs to prevent biomolecule denaturation by EcoRV restriction enzymes as well as premature release. The pH-responsive breakdown of the polymer enabled controlled intracellular release of the plasmid and knock-in of the paxillin gene sequence. However, due to the low encapsulation efficiency and complex assembly process, there is a need to develop new porous vectors that can be easily prepared, have better drug and biomolecular loading capacity, and have better biocompatibility and biodegradability.

Therefore, metal-organic frameworks (MOFs) with good biocompatibility are used for drug delivery. By post-synthetic modification with disulfide anhydride and folic acid, MOFs with redox-responsive and tumor-targeting properties were constructed as a dual-drug carrier, exhibiting synergistic enhanced anticancer effects. However, pre-prepared MOFs have the same problems as MSNs in delivering biomolecules, and the encapsulation of MOFs with postsynthetic modification provides limited protection for biomolecules. Biomimetic mineralisation technique, which has been extensively studied for inorganic systems, was applied to the synthesis of MOFs to wrap and protect biomolecules, such as the encapsulation of CRISPR-Cas9 plasmids into MOFs, where controlled nanostructures were synthesised in situ through a biomolecule-mediated strategy. The structure-function relationship studies showed that the nanostructures of the MOF coatings greatly influence the biological properties of the contained biomolecules through different embedding structures. With the help of the superior ZIF-8 vector, the GFPtagged paxillin genomic sequence was successfully knocked in a cancer cell line with high transfection potency. In addition, microfluidic-assisted biomineralization strategy for MOFs was utilised for efficient delivery and remote regulation of CRISPR-Cas9 ribonucleic acid protein (RNP)-based gene editing. By tuning different microfluidic parameters, well-defined and comparable RNP-encapsulated nanocarriers were obtained with high delivery efficiency, significant protection and NIR-responsive release, endosomal escape and precise gene knock-down capabilities.
  • Zhang, Hongbo, Valvoja
  • Rosenholm, Jessica, Valvoja
Painoksen ISBN 978-952-12-4144-4
Sähköinen ISBN 978-952-12-4145-1
TilaJulkaistu - 2022
OKM-julkaisutyyppiG5 Tohtorinväitöskirja (artikkeli)


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