Research On DNA Nanostructure-Based Smart Drug Delivery Systems

Despite conventional drug delivery systems（DDSs）with relatively high delivery efficiency and improved therapeutic efficacy,it is still challenging to construct smart DDSs allowing for precise drug release in tumor cells in a controllable manner.On the basis of Watson-Crick base-pairing rules,DNA-based nanomaterials with precise spatial addressability,site-specific surface functionality,and predesigned and programmable structures enable the realization of specific tumor recognition,precise drug release,and customized therapeutic functions.Aiming for precisely tunning the drug release of DDSs,we took advantage of DNA nanotechnology to develop DNA toehold switch-engineered spherical nucleic acid-templated hydrogels,construct mesoporous silica nanoparticle-based nanoplatforms with DNA-programmable chemical bond,and develop biomineralized DNA hydrogels by metal organic framework for enhanced chemodynamic therapy.1.Spherical nucleic acid-based hydrogel（SNAgel）was developed by utilizing AuNPs as template and taking advantage of hybridization chain reaction.Burst release of payloads can be achieved by designing ligand-specific toehold sequences on SNAgel,and the drug release kinetics with a wide range of t_1/2 ranging from 5 to 60 min can be dynamically controlled by varying the length of toehold from 3 nt to 15 nt.The camouflage of SNAgels with compact DNA shell enables elongated/prolonged blood circulation and targeted accumulation,cell entry,and apoptosis induction in vivo.The enhanced anticancer activity of SNAgels was substantiated in both cancer cell lines and xenografted tumor-bearing mice.This DNA-engineered kinetic control approach sheds new light on developing paradigm-shifting DDSs for cancer therapeutics.2.Mesoporous silica nanoparticle（MSNP）-based nanoplatforms that enables DNA-programmable chemical bond tuning drug release was constructed for treatment of multidrug resistance（MDR）cancer.By incorporating disulfide linkages into DNA building units,DNA shell-camouflaged MSNPs（MSNP@DNA）are bestowed with redox-responsiveness,thereby facilitating selective release of loaded cargo in cancer cells.Moreover,it is accessible to achieve tunable release rate by varying the density of disulfide bonds in the DNA shell,keeping the adequate drug concentration within its therapeutic window.Both in vitro and in vivo assays demonstrated that co-delivery of DOX and siRNA by MSNP@DNA and quick release of drugs can enhance therapeutic effect on MDR cancer by making drug efflux pump inoperative and facilitating DOX accumulation in the nucleus.This therapeutic nanoplatform with tunable drug release provides a good paradigm for treatment of MDR cancer.3.Metal organic framework（MOF）-biomineralized DNA hydrogels was developed as chemodynamic therapy（CDT）agent.As a result of tumor acid-induced dissociation of CDT agent,the released Fe²⁺/Fe³⁺triggers Fenton reaction to produce·OH and the released GOx enables to catalyze glucose into H₂O₂.By exploitation of tumor acid-activable cascade reactions for boosting the intracellular H₂O₂ concentration,our CDT agent enables synergistically elevating the ROS level in tumor cells and thus achieving remarkable antitumor outcome.Both in vitro and in vivo assays confirmed that our CDT agent achieves prominent therapeutic efficacy.Our work provides a promising strategy to develop CDT agents for improving CDT efficacy.These studies provide examples and guidance for the design of DNA nanostructure-based smart DDSs,the improvement of accurate drug release,and the realization of more precise cancer treatment.Additionally,these design strategies also provide flexible and powerful platforms for mechanism research and potential clinical applications.