Aptamers with high affinity and specificity are powerful molecular tools in the fields of diagnostic and therapeutic.However,natural aptamers are highly susceptible to nucleases degradation in vivo applications.Though existing methods can improve the global biostability of aptamers via the introduction of modified nucleotides,aptamers are usually expected to function only in lesions area but useless in unappointed region from clinical purposes.Herein,we report that the molecular tail-protection design（MTD） enhances the biostability of natural aptamers in the tumor microenvironment.In MTD,a split ATP aptamer was separately embedded into both ends of targeted aptamers,termed MT-aptamers,which would bind to ATP molecules from the tumor microenvironment and thus resistant to nucleases degradation.Thermal stability,nuclease resistance and in vivo fluorescence imaging analysis of MT-aptamers showed that MT-aptamers biostability was significantly improved without compromising aptamer binding properties,specifically prolonging MT-aptamers circulation time in tumor model.Besides,the universality of MTD was also verified by another three MT-aptamers model.Therefore,the MTD provides a simple and universal method to specifically enhance the biostability of natural aptamers without introducing any modified elements,accelerating the development of aptamer applications in vivo.

Cancer stem-like cells play a key role in tumor development,which contributes to tumor occurrence and post-treatment relapse.Hence,concurrent elimination of bulk tumor cells and highly tumorigenic cancer stem-like cells（CSCs） as a promising strategy has been evidenced to significantly improve cancer therapy.Here we show that a multifunctional assembly of biomimetic nanovesicles can self-adaptively transform its particulate property in response to tumor microenvironment-associated signals to overcome the sequential barriers and achieve an enhanced antitumor efficacy by killing CSCs and bulk tumor cells synchronously.Therefore,a multifunctional assembly of biomimetic nanovesicles for drug delivery with potential biomedical application in cancer therapeutics.

Dynamic and precise control of protein behaviors is critical to dissect protein-dominant signaling networks in living cells.However,it remains challenging to reversibly manipulate the behaviors of native proteins.Here,we report an aptamer-based nanoclaw to reversibly regulate the behaviors of CD28,one of the costimulatory proteins for T lymphocytes activation,enabling precise control of the cellular immune response changes during living T cell activation.The CD28 aptamers connected on the nanoclaw can specifically bind to CD28,whose distance between proteins could be adjusted by using DNA strands to drive the changes in opening/closing state of the nanoclaw.Therefore,the distance changes of CD28 on cell membranes and the regulation of downstream activation pathways were realized,providing a novel strategy for reversible study of the natural protein roles of complex signaling pathways in living cells.