DNA-controlled Dynamic Assembly Of Nanoparticles For Cancer Therapy

In cancer therapy,the delivery efficiency of drug toward tumor site directly determine its treatment effect.The inadequate accumulation of drug among tumor tissue will not only affect the antitumor efficacy,but also cause side effects on normal tissues and organs,which may seriously threaten the health of patients.Nanomedicines have been widely used in cancer therapy for decades because of their outstanding physicochemical properties and functional potential,especially the better transportation efficiency toward tumor site due to enhanced penetration and retention(EPR)effect.However,in recent years,it’s generally realized that traditional nanomedicines with fixed size cannot perfectly reconcile the demands of each transportation process such as accumulation and penetration.Thus,it’s necessary to develop new kinds of nanomedicines with dynamic size.Concerning the plenty advantages of DNA materials such as the ease of functionalization,the rich responsiveness and outstanding designability,the dynamic assembly/disassembly platform based on DNA-modified gold nanoparticles was constructed and explored its potential for cancer therapy.The detailed researches are given as follows:1.pH-responsive DNA induced intracellular assembly of nanoparticles for cancer therapyi-motif DNA with pH responsiveness was modified to gold nanoparticles(AuNPs),to trigger the intracellular assembly of nanoparticles among acidic condition of lysosome.The anti-cancer drug doxorubicin(DOX)was loaded in duplex DNA,and could be released during the assembly process due to the conformation switch of DNA strands.Meanwhile,near-infrared(NIR)photothermal therapy function of AuNPs was also activated because of nano-assembly formation.Besides,polyethylene glycol(PEG)was conjugated to nanoparticles together through metalloproteinase-2(MMP-2)sensitive peptide(pep-PEG),to hinder the non-specific recognition between nanoparticles.Once the peptide was hydrolyzed with MMP-2 among tumor site,the pH-induced assembly and corresponding therapeutic functions could be activated.The results showed that the formation of nano-assemblies successfully happened at pH 5.0,leading to DOX release and photothermal conversion effect simultaneously.The in-situ assembly also enhanced the retention behavior of nanoparticles.Besides,through modification of pep-PEG,an MMP-2 responsive activation of in-situ assembly function was endowed,resulting in an enhanced tumor specificity of therapy.2.mRNA guided intracellular assembly of nanoparticles for specific cancer therapyTwo thiolated DNA strands complementary to adjacent segments in survivin mRNA,which was overexpressed in cancer cells,were modified to AuNPs respectively,so that the target sequence in mRNA could act as linker of AuNP-DNA conjugates,leading to formation of intracellular assemblies.The result showed that NIR photothermal conversion effect was activated by assemlby of AuNPs,which helped improve the accuracy and safety of photothermal therapy.Besides,the expression level of survivin mRNA was also interfered and eventually resulted in apoptosis upregulation of cancer cells.The retention performance was significantly promoted due to the increased size of AuNP assembly,which was conducive to the gene regulation effect and subsequent photothermal efficiency.3.Dual-responsive DNA regulated in-situ disassembly of nanoparticles and cancer specific drug releaseThe pH-responsive triplex DNA and its binding sequence were modified to AuNP surface separately,to construct the pH-sensitive nano-assembly which can realize insitu disassembly among tumor tissue acidic condition.By further combination of the telomerase-sensitive hairpin DNA loaded with chemotherapy drug DOX,a cancer specific intracellular drug release function was also realized,and resulting in a precise treatment effect and lower toxicity on normal cells.Through co-modification of these two structure-switchable DNA chains on AuNPs and construction of nanoparticle assemblies with proper size,programmed disassembly and drug release function in tissue and cell level respectively were combined,and eventually facilitated a highly efficient nano-drug transportation process,from tumor accumulation to deep penetration and precise cancer chemotherapy.