Interfacially Engineered Theranostic Nanodevices Constructed By Polydopamine And Nucleic Acids

Benefiting from the remarkable advances of nanotechnology,a large number of theranostic nanodevices have been developed.The tumor detection/imaging strategies,gene therapy strategies and nano-catalysis therapy strategies based on the combination of nanomaterials and functional nucleic acids（i.e.aptamer and genetic medicine）exhibited great application potential.Despite all the advantages of these reported studies,some essential challenges still exist for them to be taken up for application.Notably,restricted signal response,low accessibility of biochemical substances and limited synergy of theranostic module caused by the low cellular abundance of biomarkers and complex physiological environment are still an enormous challenge.By introduction of polydopamine（PDA）nanomaterials with photothermal activity,interfacial activity,and chemical reactivity,and by sequence design of nucleic acids for endowing them with stimulus responsibility and spatial information may solve the problems above.Therefore,based on the interface engineering technologies,this paper constructed a series of theranostic nanodevices.The precise structural regulation of polydopamine and the behavior regulation of nucleic acid molecules were realized through utilizing the interface interaction between polydopamine and nucleic acid.By coupling the structures with functions,the efficient gene delivery,the sensitive and specific tumor detection and imaging,the high spatiotemporal resolution of photothermal therapy,and high controllable nano-catalytic therapy were achieved.PDA nanoparticles could act as nanoquenchers for fluorescent mi RNA detection,owing to the advantages of PDA including fluorescence quenching ability,non-covalent binding through the multi-siteπ-πstaking between the aromatic units of PDA and nucleobases of single stranded（ss）DNA,as well as the electrostatic repulsion between PDA and negatively charged oligonucleotides.In this system,a sensitive mi RNA sensing strategy using large-pore-sized mesoporous polydopamine nanoparticles（MPDA-L）and DNase I was established.The mesoporous effectively protected the probe DNA from cleavage by DNase I which was used for signal amplification.Moreover,compared with small-pore-sized MPDA and PDA nanospheres,enhanced DLVO（Derjaguin–Landau–Verwey–Overbeek）repulsion generated inside the pore surface of MPDA-L by the negative surface-curvature effect greatly improved differential affinity of ss DNA and mi RNA/probe heteroduplex（1.5–2.4-fold）,which is conducive to improve the detection sensitivity（1.6–2.2-fold）and lower the detection limit（32 p M）.The developed strategy can be successfully applied to quantify mi RNA in cancer cells by using total RNA samples from cell lysate.The detection specificity was further improved and therapeutic functions were introduced for constructing theranostic nanodevices which could be applied in complex physiological environments.In this system,a“dual-key-one-lock”nanodevice was built by loading thermo-activatable DNA hybridization probe（TAHP）into MPDA-based multifunctional nanotransducer（photothermal conversion agent,fluorescence quencher,and probe host）,enabling precisely switchable theranostic operations under the co-activation of exo/endogenous stimulations（near-infrared（NIR））.In TAHP,mi RNA-sensing strand bound a short switching strand（S DNA）mask to form a“shielded”internal toehold and duplex region of moderate melting temperature（45℃）,as well as a linker strand for anchoring in the mesoporous of MPDA.Under irradiation with NIR laser,the photothermal conversion triggered the thermos-responsive release of S DNA and thus activate the toehold mediated strand displacement reaction by the exposed toehold.By reduced nonspecific activation,this dual factor co-activatable nanodevices exhibited a high tumor-to-background ratio value of 8.9,as well as a significantly lower（6–9-fold）normal tissue fluorescence as compared with those sensing mi RNA solely.Moreover,the tumors were significantly suppressed after the photothermal therapy with the assistance of the accurate mi RNA diagnosis.In order to improve lysosomal escape efficiency,controllability of gene delivery,and safety of nanocarrier,a si RNA-delivery and PTT system of hybrid MPDA integrating functions of biomimetic wet-adhesion and biomineralization encapsulation was constructed.MPDA with a high photothermal conversion efficiency of 37%modified with tertiary amines to realize high si RNA loading capacity（10 wt%）.Moreover,calcium phosphate（Ca P）coating via biomineralization was constructed on the cationic MPDA to prohibit premature release of si RNA.The Ca P coating underwent biodegradation in weakly-acidic lysosomes condition.Thus,the synergistic integration of tertiary amines and catechol moieties on the subsequently exposed surfaces was demonstrated to feature a high lysosomal escape efficiency via the greatly enhanced interfacial adhesion and interactions.When an efficient knocking down（65%）of survivin was combined with the subsequent photothermal ablation,remarkably higher therapeutic efficiencies were observed both in vitro and in vivo.Besides the interfacial adhesion,the redox activity and polymerization of PDA was also regulated by host-guest supramolecular interactions between G-quadruplexes and PDA oligomers.Herein,G-quadruplexes/hemin（GH）complexes with largeπ-planes of bases and interplane spaces provided steric protection for the semiquinone radicals-containing PDA oligomers.Besides,theπ-πinteraction between PDA oligomers and G-tetrads further stabilized semiquinone radicals through the delocalization of spin density.Moreover,semiquinone radicals served as electron donor to oxygen for generating H₂O₂ which could be utilized by the neighboring GH to generate hydroxyl radicals（·OH）at weakly acidic conditions.The cascade catalytic activity remained above 93%and 45%after 20,60 days of storage in N₂ saturated solution.However,it was consumptively attenuated（～22 h of dissipation duration）due to the electron exhaustion of semiquinone radicals at pathological conditions.Thereby,effective inhibition of tumor recurrence and wound infection,as well as avoiding long-last inflammation were achieved in tumor postoperative treatments.In conclusion,a series of theranostic nanodevices was established based on the interfacial interaction between PDA and nucleic acids for mi RNA detection,tumor imaging,gene-photothermal therapy,and nano-catalytic therapy.Enhanced DLVO repulsion caused by the negative surface-curvature effect inside the mesoporous surface for improving sensitivity of mi RNA sensing was discovered.A precisely switchable theranostic nanodevice under the co-activation of exo/endogenous stimulations for specific tumor imaging and imaging guided PTT was established.Biomimetic wet-adhesion and biomineralization induced by the synergistic integration of tertiary amines and catechol moieties contribute to lysosomal escape and gene-photothermal therapy was illustrated.A ternary composite nanostructure based on host-guest supramolecular interaction between DNAzymes and PDA for dissipative·OH generation and tumor postoperative treatments was developed.This paper provided an important paradigm for constructing nanodevices with properties of sensitivity and specificity,efficient and safe,as well as energy coupling,though regulating interface activity of nanomaterials,which were expected to expand the significant applications in clinical.