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The chiral amplification effects within the enantiomeric and diastereomeric copolymer series can be regulated, resulting in a controllable P or M helix preference, which can be applied in smart chiral materials with helix-regulable desires.

The curvature-mediated interactions by cell membranes are crucial in many biological processes. We systematically studied the curvature-mediated wrapping of soft nanoparticles (NPs) by a tensionless membrane and the underlying pair interactions between NPs in determining it. We found that there are three types of wrapping pathways, namely, independence, cooperation, and tubulation. The particle size, adhesion strength, and softness are found to be strongly related with the wrapping mechanism. Reducing the adhesion strength transforms the wrapping pathway from cooperation to independence, while enhancing the NP softness requires a stronger adhesion to achieve the cooperative wrapping. This transformation of the wrapping pathway is controlled by the curvature-mediated interactions between NPs. For either soft or rigid NPs, the pair interactions are repulsive at short-ranged distances between NPs, while at long-ranged distances, a larger adhesion between NPs and a membrane is needed to generate attraction between NPs. Moreover, an enhancement of NP softness weakens the repulsion between NPs. These distinct behaviors of soft NPs are ascribed to the gentler deformation of the membrane at the face-to-face region between NPs due to the flattening and spreading of soft NPs along the membrane, requiring a reduced energy cost for soft NPs to approach each other. Our results provide a mechanistic understanding in detail about the membrane-mediated interactions between NPs and their interactions with cell membranes, which is helpful to understand the curvature-mediated assemblies of adhesive proteins or NPs on membranes, and offer novel possibilities for designing an effective NP-based vehicle for controlled drug delivery.

Nitric oxide (NO) serves as a key regulator of many physiological processes and as a potent therapeutic agent. The local delivery of NO is important to achieve target therapeutic outcomes due to the toxicity of NO at high concentrations. Although light stimulus represents a non-invasive tool with spatiotemporal precision to mediate NO release, many photoresponsive NO-releasing molecules can only respond to ultraviolet (UV) or near-UV visible light with low penetration and high phototoxicity. We report that coumarin-based NO donors with maximal absorbances at 328 nm can be activated under (deep) red-light (630 or 700 nm) irradiation in the presence of palladium(II) tetraphenyltetrabenzoporphyrin, enabling stoichiometric and self-reporting NO release with a photolysis quantum yield of 8 % via photoredox catalysis. This NO-releasing platform with ciprofloxacin loading can eradicate Pseudomonas aeruginosa biofilm in vitro and treat cutaneous abscesses in vivo.

Photoredox catalysis has emerged as a robust tool for chemical synthesis. However, it remains challenging to implement photoredox catalysis under physiological conditions due to the complex microenvironment and the quenching of photocatalyst by biologically relevant molecules such as oxygen. Here, we report that UV-absorbing N,N'-dinitroso-1,4-phenylenediamine derivatives can be selectively activated by fac-Ir(ppy)

Toehold-mediated strand displacement reaction, the fundamental basis in dynamic DNA nanotechnology, has proven its extraordinary power in programming dynamic molecular systems. Programmed activation of the toehold in a DNA substrate is crucial for building sophisticated DNA devices with digital and dynamic behaviors. Here we developed a detachable DNA circuit by embedding a pH-controlled intermolecular triplex between the toehold and branch migration domain of the traditional "linear substrate". The reaction rate and the "on/off" state of the detachable circuit can be regulated by varying the pHs. Similarly, a two-input circuit composed of three pH-responsive DNA modules was then constructed. Most importantly, a resettable self-assembly system of spherical nucleic acids was built by utilizing the high detachability of the intermolecular triplex structure-based DNA circuit. This work demonstrated a dynamic DNA device that can be repeatedly operated at constant temperature without generating additional waste DNA products. Moreover, this strategy showed an example of recycling waste spherical nucleic acids from a self-assembly system of spherical nucleic acids. Our strategy will provide a facile approach for dynamic regulation of complex molecular systems and reprogrammable nanoparticle assembly structures.

End modification of the toehold domain or near to it using fluorophore dyes or quenchers can significantly modulate the kinetics of the toehold-mediated strand displacement reaction (TMSDR) by almost two orders of magnitude. The labels at the end of the signal strand impede the TMSDR, while those at the end of the toehold domain of the substrate strand accelerate the TMSDR kinetics.

To report the overall prevalence of social frailty among older people and provide information for policymakers and authorities to use in developing policies and social care.A systematic review and meta-analysis.We searched 4 databases (PubMed, Embase, Web of Science, and Google Scholar) to find articles from inception to July 30, 2022. We included cross-sectional and cohort studies that provided the prevalence of social frailty among adults aged 60 years or older, in any setting.Three researchers independently reviewed the literature and retrieved the data. A risk of bias tool was used to assess each study's quality. A random-effect meta-analysis was performed to pool the data, followed by subgroup analysis, sensitivity analysis, and meta-regression.From 761 records, we extracted 43 studies with 83,907 participants for meta-analysis. The pooled prevalence of social frailty in hospital settings was 47.3% (95% CI: 32.2%-62.4%); among studies in community settings, the pooled prevalence was 18.8% (95% CI: 14.9%-22.7%; P.001). The prevalence of social frailty was higher when assessed using the Tilburg Frailty Indicator (32.3%; 95% CI: 23.1%-41.5%) than the Makizako Social Frailty Index (27.7%; 95% CI: 21.6%-33.8%) or Social Frailty Screening Index (13.4%; 95% CI: 8.4%-18.4%). Based on limited community studies in individual countries using various instruments, social frailty was lowest in China (4.9%; 95% CI: 4.2%-5.7%), followed by Spain (11.6%; 95% CI: 9.9%-13.3%), Japan (16.2%; 95% CI: 12.2%-20.3%), Korea (26.6%; 95% CI: 7.1%-46.1%), European urban centers (29.2%; 95% CI: 27.9%-30.5%), and the Netherlands (27.2%; 95% CI: 16.9%-37.5%). No other subgroup analyses showed any statistically significant prevalence difference between groups.The prevalence of social frailty among older adults is high. Settings, country, and method for assessing social frailty affected the prevalence. More valid comparisons will await consensus on measurement tools and more research on geographically representative populations. Nevertheless, these results suggest that public health professionals and policymakers should seriously consider social frailty in research and program planning involving older adults.

A small molecule, as a catalytic assembler, can promote the assembly of a diblock polymer in a thin film into an ordered structure.

Catalytic hairpin assembly (CHA) is a typical enzyme-free amplification strategy, in which the target can catalyze two hairpin probes to form a duplex and yield multiple outputs signal. However, the non-specific hybridization of two hairpin probes in CHA circuit usually occurred even in the absence of target, causing significant background leakage and impeding its practical applications in trace miRNA analysis. Herein, we proposed a novel heterogeneous CHA (hetero-CHA) design integrating with PDA microtube waveguide system, offering the advantages to enhance the target signal, but suppress the background leakage simultaneously. In hetero-CHA strategy, single-stranded targets are enriched nearby the surface of PDA microtube, facilitating the target-triggered CHA amplification and strand displacement reactions. In contrast, double-stranded DNA complexes formed by uncatalyzed hybridizations are isolated from PDA microtube, impeding the leakage signal. By combination with condensing enrichment effect, the proposed hetero-CHA probe exhibited high selectivity and sensitivity to miRNA target, giving a detection limit as low as 3.3 fM. More importantly, the proposed hetero-CHA probe can be applied directly to distinguish the expression of miRNA-21 in clinical serum of cancer patients (including lung, breast and pancreatic) from those of healthy human beings, favoring the cancer diagnosis and therapeutic evaluation.

Prevention of metastatic and local-regional recurrence of cancer after surgery remains difficult. Targeting postsurgical premetastatic niche and microresiduals presents an excellent prospective opportunity but is often challenged by poor therapeutic delivery into minimal residual tumors. Here, an enzymatically transformable polymer-based nanotherapeutic approach is presented that exploits matrix metalloproteinase (MMP) overactivation in tumor-associated tissues to guide the codelivery of colchicine (microtubule-disrupting and anti-inflammatory agent) and marimastat (MMP inhibitor). The dePEGylation of polymersomes catalyzed by MMPs not only exposes the guanidine moiety to improve tissue/cell-targeting/retention to increase bioavailability, but also differentially releases marimastat and colchicine to engage their extracellular (MMPs) and intracellular (microtubules) targets of action, respectively. In primary tumors/overt metastases, the vasculature-specific targeting of nanotherapeutics can function synchronously with the enhanced permeability and retention effect to deter malignant progression of metastatic breast cancer. After the surgical removal of large primary tumors, nanotherapeutic agents are localized in the premetastatic niche and at the site of the postsurgical wound, disrupting the premetastatic microenvironment and eliminating microresiduals, which radically reduces metastatic and local-regional recurrence. The findings suggest that nanotherapeutics can safely widen the therapeutic window to resuscitate colchicine and MMP inhibitors for other inflammatory disorders.

Plasma membrane rupture is a promising strategy for drug-resistant cancer treatment, but its application is limited by the low tumour selectivity of membranolytic molecules. Here we report the design of 'proton transistor' nanodetergents that can convert the subtle pH perturbation signals of tumour tissues into sharp transition signals of membranolytic activity for selective cancer therapy. Our top-performing 'proton transistor' nanodetergent, P(C6-Bn

Homogeneous DNA-only keypad locks were built with multi-stranded scalable junction substrates and a series of double-stranded eliminators to differentially process correctly- and wrongly-added DNA inputs, respectively. Unlike conventional strategies that employed solid-phase platforms, one-pot assay of multiple DNA inputs was achieved, showing merits in fabricating complicated information security systems.

Unwanted initial and asymptotic leakages are vital to fabricating integrated circuitries. This paper presents a novel strategy that combines simulations and experiments to extend the circuitries of spherical nucleic acid (SNA) to three layers. The results indicate that SNA-based circuits are insensitive to initial leakage but are significantly influenced by asymptotic leakage, particularly for the two-layer circuit. The dynamic behaviors of and the effects of leakage on the performance of the integrated system can be regulated by fine tuning of toehold domains and the molar ratio of the species. Small upstream layers and a large downstream layer are experimentally adopted to balance the stability and operation efficiency of the integrated three-layer circuitry. This work soundly demonstrates the capability of fabricating modular cascaded circuitry for driving SNA assembly in sophisticated systems, and modulating or programming the molecular machinery for developing an autonomous system.

As a strategy for regulating entropy, thermal annealing is a commonly adopted approach for controlling dynamic pathways in colloid assembly. By coupling DNA strand-displacement circuits with DNA-functionalized colloid assembly, we developed an enthalpy-mediated strategy for achieving the same goal while working at a constant temperature. Using this tractable approach allows colloidal bonding to be programmed for synchronization with colloid assembly, thereby realizing the optimal programmability of DNA-functionalized colloids. We applied this strategy to conditionally activate colloid assembly and dynamically switch colloid identities by reconfiguring DNA molecular architectures, thereby achieving orderly structural transformations; leveraging the advantage of room-temperature assembly, we used this method to prepare a lattice of temperature-sensitive proteins and gold nanoparticles. This approach bridges two subfields: dynamic DNA nanotechnology and DNA-functionalized colloid programming.

Versatile building blocks are essential for building complex and scaled-up DNA circuits. In this study, we propose a conceptually new scalable architecture called a "junction substrate" (J-substrate) that is linked by prepurified double-stranded DNA molecules. As a proof-of-concept, this novel type of substrate has been utilized to build multi-input DNA circuits, offering several advantages over the conventional substrate (referred to as a "linear substrate", L-substrate). First, the J-substrate does not require long DNA strands, thus avoiding significant synthetic errors and costs. Second, the traditional PAGE purification method is technically facilitated to obtain high-purity substrates, whereby the initial leakage is effectively eliminated. Third, the asymptotic leakage is eliminated by introducing the "junction". Finally, circuits with the optimized J-substrate architecture exhibit fast kinetics. We believe that the proposed architecture constitutes a sophisticated chassis for constructing complex circuits.

Herein, we designed and prepared a photoresponsive spherical nucleic acid (SNA) conjugate by inserting a photocleavable linker into the recognition sequence of SNA which can block the reactivity of the system temporally until specific UV light (∼365 nm) is introduced. The photoresponsive SNA realizes temporal regulation of a self-assembly reaction circuit and spatial selectivity of microRNA release in a cell population, respectively.

Understanding the interactions of nanoparticles (NPs) with cell membranes and regulating their cellular uptake processes are of fundamental importance to the design of drug delivery systems with minimum toxicity, high efficiency and long circulation time. Employing the procedure of coarse-graining, we built an elastically deformable NP model with tunable morphological and mechanical properties. We found that the cellular uptake of deformable NPs depends on their shape: an increase in the particle elasticity significantly slows the uptake rate of spherical NPs, slightly retards that of prolate NPs, and promotes the uptake of oblate NPs. The intrinsic mechanisms have been carefully investigated through analysis of the endocytic mechanisms and free energy calculations. These findings provide unique insights into how deformable NPs penetrate across cell membranes and offer novel possibilities for designing effective NP-based carriers for drug delivery.

The mechanics of DNA bending is crucially related to many vital biological processes. Recent experiments reported anomalous flexibility for DNA on short length scales, calling into doubt the validity of the harmonic worm-like chain (WLC) model in this region. In the present work, we systematically probed the bending dynamics of DNA at different length scales. In contrast to the remarkable deviation from the WLC description for DNA duplexes of less than three helical turns, our atomistic studies indicate that the neutral "null isomer" behaves in accord with the ideal elastic WLC and exhibits a uniform decay for the directional correlation of local bending. The backbone neutralization weakens the anisotropy in the effective bending preference and the helical periodicity of bend correlation that have previously been observed for normal DNA. The contribution of electrostatic repulsion to stretching cooperativity and the mechanical properties of DNA strands is length-scale-dependent: the phosphate neutralization increases the stiffness of DNA below two helical turns, but it is decreased for longer strands. We find that DNA rigidity is largely determined by base pair stacking, with electrostatic interactions contributing only around 10% of the total persistence length.

To date, implementation of renewable DNA circuits remains challenging due to issues including reactant depletion and waste accumulation. Herein we simultaneously addressed both issues through nicking enzyme-assisted waste-to-reactant transformation. As a proof-of-concept, a renewable entropy-driven catalytic DNA circuit was implemented, exhibiting a good renewability when replenishing fuel.

The synthetic DNA hybridization probe has proved its importance in biology and biotechnology. In this study, taking advantage of a novel analytical technique called dual polarization interferometry (DPI), the influence of the toehold strategy of on-chip DNA hybridization probe on the discrimination of single nucleotide polymorphism (SNP) was investigated. Through adjusting the toehold length, the toehold strategies of on-chip toehold exchange probe were thoroughly optimized. For the “6/5” probe, an optimal discrimination factor of 78% against the spurious target was achieved. Moreover, the ability of the on-chip probe in SNP discrimination was significantly enhanced compared to its pure solution counterpart. This simple and rapid detection method for SNP discrimination based on the on-chip toehold exchange probe will show great potential in disease diagnosis.

The fabrication of DNA polymer brushes with spatial resolution onto a solid surface is a crucial step for biochip research and related applications, cell-free gene expression study, and even artificial cell fabrication. Here, for the first time, a DNA polymer brush patterning method is reported based on the photoactivation of an ortho-nitrobenzyl linker-embedded DNA hairpin structure and a subsequent surface-initiated DNA hybridization chain reaction (HCR). Inert DNA hairpins are exposed to ultraviolet light irradiation to generate DNA duplexes with two active sticky ends (toeholds) in a programmable manner. These activated DNA duplexes can initiate DNA HCR to generate multifunctional patterned DNA polymer brushes with complex geometrical shapes. Different multifunctional DNA polymer brush patterns can be fabricated on certain areas of the same solid surface using this method. Moreover, the patterned DNA brush surface can be used to capture target molecules in a desired manner.

Cononsolvency is a phenomenon for which the solubility of a macromolecule decreases or even vanishes in the mixture of two good solvents. Although it has been widely applied in physicochemical, green chemical and pharmaceutical industry, its origin is still under active debate. Here, by using combined neutron total scattering, deuterium-labelling and all-atom molecular dynamic simulations, we demonstrated that it is the strong water/cosolvent attraction that leads to the cononsolvency. The combined approach presented here has opened a new route for investigating the most probable all-atom structure in macromolecular solutions and the thermodynamic origin of solubilities., Comment: 27 pages 10 figures with supporting infomation attached

Smart nanocarriers attract considerable interest in the filed of precision nanomedicine. Dynamic control of the interaction between nanocarriers and cells offers the feasibility that in situ activates cellular internalization at the targeting sites. Herein, we demonstrate a novel class of enzyme-responsive asymmetric polymeric vesicles self-assembled from matrix metalloproteinase (MMP)-cleavable peptide-linked triblock copolymer, poly(ethylene glycol)-GPLGVRG-b-poly(ε-caprolactone)-b-poly(3-guanidinopropyl methacrylamide) (PEG-GPLGVRG-PCL-PGPMA), in which the cell-penetrating PGPMA segments asymmetrically distribute in the outer and inner shells with fractions of 9% and 91%, respectively. Upon treatment with MMP-2 to cleave the stealthy PEG shell, the vesicles undergo morphological transformation into fused multicavity vesicles and small nanoparticles, accompanied by redistribution of PGPMA segments with 76% exposed to the outside. The vesicles after dePEGylation show significantly increased cellular internalization efficiency (∼10 times) as compared to the original ones due to the triggered availability of cell-penetrating shells. The vesicles loading hydrophobic anticancer drug paclitaxel (PTX) in the membrane exhibit significantly enhanced cytotoxicity against MMP-overexpressing HT1080 cells and multicellular spheroids. The proposed vesicular system can serve as a smart nanoplatform for in situ activating intracellular drug delivery in MMP-enriched tumors.

The toehold-mediated DNA-strand-displacement reaction has unique programmable properties for driving the catalytic assembly of gold nanoparticles (AuNPs). Herein, we introduced a pH-responsive triplex structure into the DNA-strand-displacement-based catalytic assembly system of DNA–AuNPs to add an additional controlling factor, namely the pH. In this catalytic system, the aggregation rate of AuNPs could be regulated by both internal factors (concentrations of substrate, target, etc.) and an external control (pH gradient). This strategy can be used to construct pH-induced DNA logic gates and sophisticated DNA networks as well as to image instantaneous pH changes in living cells.

Other than being a carrier of the code of life deoxyribonucleic acid (DNA) can also be used as a kind of ideal biomaterial with good biocompatibility. The basis of DNA dynamic nanotechnology is the toehold-mediated strand displacement reactions. Utilizing the specificity and predictability of Watson–Crick base pairing, and the programmability of the base sequence of DNA, researchers can construct the molecular machine and precisely control its operation to realize various complex molecular calculations. In this paper, we reviewed the progress of DNA structure and mechanical properties in recent years, discussed the microcosmic mechanism of DNA strand replacement reaction, and introduced the latest achievements in DNA molecular computing and its application in DNA constant temperature self-assembly.

Internalization of nanoparticles by biomembranes is critical for nanomedicine development; however, this process, especially its dynamics aspect, is still not well understood. Using coarse-grained molecular modeling combined with free energy calculations, we studied the endocytic process for spherical, prolate and oblate particles with varied aspect ratios, volumes and interaction strengths. Rich dynamic wrapping behaviors have been observed. Small ellipsoids follow a pathway that includes particle laying-down, membrane invagination and wrapping, and then disruption of the membrane neck. However, the step of particle laying-down is skipped for large ellipsoids. Because of the significantly decreased local mean curvature at the side edge (oblate ellipsoid) or tips (prolate ellipsoid), the rotation is less favorable for particles with larger volume. Given the existence of a local minimum and an energy barrier during the endocytic process presented by our free energy calculations, the oblate particle provides longer endocytic time than the corresponding prolate particle. For large particles, the free energy surfaces are smooth, with no local minimum. When we increase the interaction strength between the membrane and the particle, the endocytic process is greatly affected. Moreover, a “sandwiched structure”, in which the particle lays between the two membrane layers, was observed for both prolate and oblate particles.

Programmable and algorithmic behaviors of DNA molecules allow one to control the structures of DNA-assembled materials with nanometer precision and to construct complex networks with digital and analog behaviors. Here we developed a way of integrating a DNA-strand-displacement circuit with self-assembly of spherical nucleic acids, wherein a single DNA strand was used to initiate and catalyze the operation of upstream circuits to release a single strand that subsequently triggers self-assembly of spherical nucleic acids in downstream circuits, realizing a programmable kinetic control of self-assembly of spherical nucleic acids. Through utilizing this method, single-nucleotide polymorphisms or indels occurring at different positions of a sequence of oligonucleotide were unambiguously discriminated. We provide here a sophisticated way of combining the DNA-strand-displacement-based characteristic of DNA with the distinct assembly properties of inorganic nanoparticles, which may find broad potential applications in the fabrication of a wide range of complex multicomponent devices and architectures.

In this work, two DNA nanodevices were constructed utilizing a DNA strand displacement reaction. With the assistance of gold nanoparticles (AuNPs) and gold nanorods (AuNRs), the autonomous reactions can be reflected from the aggregation states of nanoparticles. By sequence design and the two non-overlapping double hump-like UV-vis spectral peaks of AuNPs and AuNRs, two logic gates with multiple inputs and outputs were successfully run with expected outcomes. This method not only shows how to achieve computing with multiple logic calculations but also has great potential for multiple targets detection.

In DNA dynamic nanotechnology, a toehold-mediated DNA strand-displacement reaction has demonstrated its capability in building complex autonomous system. In most cases, the reaction is performed in pure DNA solution that is essentially a one-phase system. In the present work, we systematically investigated the reaction in a heterogeneous media, in which the strand that implements a displacing action is conjugated on gold nanoparticles. By monitoring the kinetics of spherical nucleic acid (SNA) assembly driven by toehold-mediated strand displacement reaction, we observed significant differences, i.e., the abrupt jump in behavior of an "off/on switch", in the reaction rate when the invading toehold was extended to eight bases from seven bases. These phenomena are attributed to the effect of steric hindrance arising from the high density of invading strand conjugated to AuNPs. Based on these studies, an INHIBIT logic gate presenting good selectivity was developed.

Total Body Irradiation (TBI) dramatically damages the BM and thymus organs, however the long-term effects of irradiation and aging on both BM cells and thymocytes are still unclear. In this study, we described that although the kinetics of thymocyte restoration was varied with the sex, dose and exposure age, a long-term and dose dependent reduction of DN1a,b progenitors and a transient over-response peak of thymocytes around 5-6 weeks were shown unanimously in all groups after irradiation, which led to the recovery of thymus maintained in a lower level of total thymocyte number through life. Such events were primarily due to the reduction of functional LSK progenitors in BM rather than the changes to the thymic environment. The damage of irradiation in BM LSK cells was dose dependent and 0.5 Gy was able to result in a significant long-term reduction of LSK progenitors. Responding to the reduction of thymocytes, both DN3 and DN4 subsets played a critical role on the compensation of the reduction of thymocytes with a periodical profile after irradiation, but the recovery potential was dramatically reduced at the age of 12 months. This study provided the evidence that the capability of LSK cells for lymphocyte production in BM is limited and can be dramatically damaged after a single dose of relatively low TBI, which consequently accelerates premature thymic aging and senescence. Our results may also be useful for the evaluation and therapeutic intervention of human TBI events.