Host-Guest Interaction Mediated Interfacial Co-Assembly of Cyclodextrin and Bottlebrush Surfactants for Precisely Tunable Photonic Supraballs.

Investigations of host-guest interactions at water-oil (w/o) interfaces are limited in single emulsion systems producing simple self-assembled objects with limited uses. Here, within hierarchically ordered water-in-oil-in-water (w/o/w) multiple emulsion droplets, interfacial self-assembly of (polynorbornene-graft-polystyrene)-block-(polynorbornene-graft-polyethylene glycol) (PNPS-b-PNPEG) bottlebrush block copolymers can be precisely controlled through host-guest interactions. α-Cyclodextrin (α-CD) in the aqueous phase can thread onto PEG side chains of the bottlebrush surfactants adsorbed at the w/o interface, leading to dehydration and collapsed chain conformation of the PEG block. Consequently, spherical curvature of the w/o internal droplets increases with the increased asymmetry of the bottlebrush molecules, producing photonic supraballs with precisely tailored structural parameters as well as photonic bandgaps. This work provides a simple but highly effective strategy for precise manipulation of complex emulsion systems applicable in a variety of applications, such as photonic pigments, cosmetic products, pesticides, artificial cells, etc.

Functional heterogeneity of IFN-γ-licensed mesenchymal stromal cell immunosuppressive capacity on biomaterials.

Mesenchymal stromal cells (MSCs) are increasingly combined with biomaterials to enhance their therapeutic properties, including their immunosuppressive function. However, clinical trials utilizing MSCs with or without biomaterials have shown limited success, potentially due to their functional heterogeneity across different donors and among different subpopulations of cells. Here, we evaluated the immunosuppressive capacity, as measured by the ability to reduce T-cell proliferation and activation, of interferon-gamma (IFN-γ)-licensed MSCs from multiple donors on fibrin and collagen hydrogels, the two most commonly utilized biomaterials in combination with MSCs in clinical trials worldwide according to ClinicalTrials.gov Variations in the immunosuppressive capacity between IFN-γ-licensed MSC donors on the biomaterials correlated with the magnitude of indoleamine-2,3-dioxygenase activity. Immunosuppressive capacity of the IFN-γ-licensed MSCs depended on the αV/α5 integrins when cultured on fibrin and on the α2/ß1 integrins when cultured on collagen. While all tested MSCs were nearly 100% positive for these integrins, sorted MSCs that expressed higher levels of αV/α5 integrins demonstrated greater immunosuppressive capacity with IFN-γ licensing than MSCs that expressed lower levels of these integrins on fibrin. These findings were equivalent for MSCs sorted based on the α2/ß1 integrins on collagen. These results demonstrate the importance of integrin engagement to IFN-γ licensed MSC immunosuppressive capacity and that IFN-γ-licensed MSC subpopulations of varying immunosuppressive capacity can be identified by the magnitude of integrin expression specific to each biomaterial.

Structurally Dynamic Hydrogels for Biomedical Applications: Pursuing a Fine Balance between Macroscopic Stability and Microscopic Dynamics.

Owing to their unique chemical and physical properties, hydrogels are attracting increasing attention in both basic and translational biomedical studies. Although the classical hydrogels with static networks have been widely reported for decades, a growing number of recent studies have shown that structurally dynamic hydrogels can better mimic the dynamics and functions of natural extracellular matrix (ECM) in soft tissues. These synthetic materials with defined compositions can recapitulate key chemical and biophysical properties of living tissues, providing an important means to understanding the mechanisms by which cells sense and remodel their surrounding microenvironments. This review begins with the overall expectation and design principles of dynamic hydrogels. We then highlight recent progress in the fabrication strategies of dynamic hydrogels including both degradation-dependent and degradation-independent approaches, followed by their unique properties and use in biomedical applications such as regenerative medicine, drug delivery, and 3D culture. Finally, challenges and emerging trends in the development and application of dynamic hydrogels are discussed.

Internet use and loneliness among older Chinese adults.

OBJECTIVES: This study examined the association between Internet use and loneliness among Chinese older adults (aged 60+) over a two-year period using nationally representative survey data from China. METHODS: Using data from the 2016 and 2018 waves of the China Longitudinal Ageing Social Survey (N = 8,059), we estimated difference-in-differences regression models to assess the association between Internet use and levels of loneliness over time. RESULTS: Compared to Internet non-users, Chinese older adults who were new Internet users, as well as those who were continuous Internet users, reported lower levels of loneliness over time (B = -0.21, p < 0.001 and B = -0.16, p < 0.001, respectively). Conversely, those Chinese older adults who used the Internet in wave 1 but then disengaged from using the Internet in wave 2 demonstrated an upward trend in loneliness over time, similar to Internet non-users (the estimate of difference-in-differences was non-significant for the comparison between disengaged-users and non-users: B = -0.03, p = 0.42). CONCLUSION: This study provided new evidence to support the potential benefits of Internet use for reducing the risk of loneliness among Chinese older adults. The findings suggested that supporting current Internet users to remain digitally engaged is as important as encouraging Internet non-users to cross the digital divide.

AUV Path Planning Considering Ocean Current Disturbance Based on Cloud Desktop Technology.

In the field of ocean energy detection, Autonomous Underwater Vehicles (AUVs) offer significant advantages in terms of manpower, resource, and energy efficiency. However, the unpredictable nature of the ocean environment, particularly the real-time changes in ocean currents, poses navigational risks for AUVs. Therefore, effective path planning in dynamic environments is crucial for AUVs to perform specific tasks. This paper addresses the static path planning problem and proposes a model called the noise net double DQN network with prioritized experience replay (N-DDQNP). The N-DDQNP model combines a noise network and a prioritized experience replay mechanism to address the limited exploration and slow convergence speed issues of the DQN algorithm, which are caused by the greedy strategy and uniform sampling mechanism. The proposed approach involves constructing a double DQN network with a priority experience replay and an exploration mechanism using the noise network. Second, a compound reward function is formulated to take into account ocean current, distance, and safety factors, ensuring prompt feedback during the training process. Regarding the ocean current, the reward function is designed based on the angle between the current direction and the AUV's heading direction, considering its impact on the AUV's speed. As for the distance factor, the reward is determined by the Euclidean distance between the current position and the target point. Furthermore, the safety factor considers whether the AUV may collide with obstacles. By incorporating these three factors, the compound reward function is established. To evaluate the performance of the N-DDQNP model, experiments were conducted using real ocean data in various complex ocean environments. The results demonstrate that the path planning time of the N-DDQNP model outperforms other algorithms in different ocean current scenarios and obstacle environments. Furthermore, a user console-AUV connection has been established using spice cloud desktop technology. The cloud desktop architecture enables intuitive observation of the AUV's navigation posture and the surrounding marine environment, facilitating safer and more efficient underwater exploration and marine resource detection tasks.

Precise Tailoring of Polyester Bottlebrush Amphiphiles toward Eco-Friendly Photonic Pigments via Interfacial Self-Assembly.

Biodegradable photonic microspheres with structural colors are promising substitutes to polluting microbeads and toxic dyes. Here, amphiphilic polyester-block-poly(ethylene glycol) bottlebrush block copolymers (BBCPs) with polylactic acid or poly(ϵ-caprolactone) as the hydrophobic block are synthesized and used to fabricate eco-friendly photonic pigments. Molecular parameters of BBCPs, including rigidity and symmetry, are precisely tailored by variation of side chain lengths, which enables effective manipulation of interfacial tension (γ). Organized spontaneous emulsion mechanism is enabled only when γ falls in a suitable range (10.6-14.3 mN m-1 ), producing ordered water-in-oil-in-water multiple emulsions and ordered porous structures. Consequently, highly saturated and tunable structural colors are observed due to coherent light scattering from the porous structures. Such photonic materials are nontoxic as confirmed by careful safety tests using aquatic model organisms.

Directed Conformational Switching of a Zinc Finger Analogue Regulates the Mechanosensing and Differentiation of Stem Cells.

The dynamic conformational changes in the secondary structures of proteins are essential to their functions and can regulate diverse cellular events. Herein we report the design of a synthetic polymer-based secondary structure analogue of a zinc finger (ZnF) by introducing a zinc coordination motif to overcome the free energy barrier predicted by theoretical calculations and fold-free polymer chains. The conformational switching between unfolded and folded state of the ZnF analogue can be triggered in situ to drastically manipulate the accessibility of conjugated cell adhesive ligands to the cell membrane receptors, thereby effectively controlling the adhesion, spreading, mechanosensing, and differentiation of stem cells. We believe that emulating the dynamic secondary structures of proteins via rational design of a folded synthetic polymer-cation complex is a promising strategy for developing bioactive materials to mediate desired cellular functions.

Sustainable Bioplastic Made from Biomass DNA and Ionomers.

Plastics play important roles in modern life and currently the development of plastic recycling is highly demanding and challenging. To relieve this dilemma, one option is to develop new sustainable bioplastics that are compatible with the environment over the whole material life cycle. We report a sustainable bioplastic made from natural DNA and biomass-derived ionomers, termed as DNA plastics. The sustainability involves all aspects of the production, use, and end-of-life options of DNA plastics: (1) the raw materials are derived from biorenewable resources; (2) the water-processable strategy is environmentally friendly, not involving high-energy consumption, the use of organic solvents, and the production of byproducts; (3) recyclable and nondestructive use is achieved to significantly prolong the service lifetime of the plastics; and (4) the disposal of waste plastics follows two green routes including the recycling of waste plastics and enzyme-triggered controllable degradation under mild conditions. Besides, DNA plastics can be "aqua-welded" to form arbitrary designed products such as a plastic cup. This work provides a solution to transform biobased hydrogel to bioplastic and demonstrates the closed-loop recycling of DNA plastics, which will advance the development of sustainable materials.

Highly Dynamic Nanocomposite Hydrogels Self-Assembled by Metal Ion-Ligand Coordination.

Hydrogels are emerging biomaterials with desirable physicochemical characteristics. Doping of metal ions such as Ca2+ , Mg2+ , and Fe2+ provides the hydrogels with unique attributes, including bioactivity, conductivity, and tunability. Traditionally, this doping is achieved by the interaction between metal ions and corresponding ligands or the direct incorporation of as-prepared metal-based nanoparticles (NPs). However, these approaches rely on a complex and laborious preparation and are typically restricted to few selected ion species. Herein, by mixing aqueous solutions of ligands (bisphosphonates, BPs), polymer grafted with ligands, and metal ions, a series of self-assembled metallic-ion nanocomposite hydrogels that are stabilized by the in situ formed ligand-metal ion (BP-M) NPs are prepared. Owing to the universal coordination between BPs and multivalent metal ions, the strategy is highly versatile and can be generalized for a wide array of metal ions. Such hydrogels exhibit a wide spectrum of mechanical properties and remarkable dynamic properties, such as excellent injectability, rapid stress relaxation, efficient ion diffusion, and triggered disassembly for harvesting encapsulated cells. Meanwhile, the hydrogels can be conveniently coated or patterned onto the surface of metals via electrophoresis. This work presents a universal strategy to prepare designer nanocomposite materials with highly tunable and dynamic behaviors.

Stimulatory Effects of Sublethal Doses of Carbendazim on the Virulence and Sclerotial Production of Botrytis cinerea.

Stimulatory effects of low doses of fungicides on the virulence of phytopathogens have profound implications for applications of fungicides. The present study demonstrated that carbendazim sprayed at 0.001 to 0.03 µg/ml had stimulatory effects on the virulence of mycelia of Botrytis cinerea, and the maximum percent stimulations were 15.5 and 21.4% for isolates HB459 and HB536, respectively. Potato dextrose agar (PDA) amended with carbendazim at 0.01, 0.02, and 0.05 µg/ml inhibited mycelial growth of isolate HB536 by 0.8, 10.0, and 30.6%, respectively. However, after the inhibited mycelia were inoculated on cucumber leaves, virulence increased by 10.1, 12.9, and 10.8%, respectively. With respect to sclerotial production, carbendazim at 0.005 and 0.02 µg/ml in PDA significantly (P < 0.05) increased, while at 0.1 µg/ml significantly (P < 0.05) reduced the sclerotial number and weight of both isolates compared with nontreated controls. Conidia germination percentages slightly yet statistically significantly (P < 0.05) increased after being inoculated on PDA amended with carbendazim at 0.001 and 0.005 µg/ml. Carbendazim at 0.001∼0.02 µg/ml, either sprayed on cucumber leaves or cosuspended with conidia, exerted significantly (P < 0.05) stimulatory effects on the virulence of B. cinerea conidia. Mechanism studies showed that sublethal doses of carbendazim did not increase the expression levels of pathogenicity-related pectin methylesterase gene Bcpme1, endopolygalacturonase gene Bcpg2, cutinase gene CutA, xylanase gene Xyn11A, or NADPH oxidase gene BcnoxA.

Pathways Linking Information and Communication Technology Use and Loneliness Among Older Adults: Evidence From the Health and Retirement Study.

BACKGROUND AND OBJECTIVES: This study investigated the association between information and communication technology (ICT) use and loneliness among community-dwelling older adults (aged 65+), as well as the mediating effects of social relations, perceived control, and purpose-in-life. RESEARCH DESIGN AND METHODS: The study used data from the 2014 and 2018 Health and Retirement Study (N = 3,026), employing autoregressive path models with contemporaneous mediation to assess the association of 2 kinds of ICT use, social media communication and general computer use, with loneliness through the pathways of perceived social support, social contact, perceived constraints, and purpose-in-life. RESULTS: Social media communication had a negative association with loneliness. Perceived social support and social contact mediated this association, but not perceived constraints, or purpose-in-life. General computer use did not have a significant total effect on loneliness; however, a significant indirect effect through perceived constraints, purpose-in-life, and social contact was found. DISCUSSION AND IMPLICATIONS: Our findings extended the existing literature regarding the important factors associated with variation in loneliness among older adults. Health programs and ICT solutions could be more effective in mitigating loneliness if they target the root causes of loneliness, including reducing perceptions of constraints and increasing a sense of purpose-in-life, along with strengthening social relationships.

Internet Use and Loneliness Among Urban and Non-Urban Chinese Older Adults: The Roles of Family Support, Friend Support, and Social Participation.

OBJECTIVES: This study investigated the association between internet use and loneliness among older Chinese adults, and the mediating effects of family support, friend support, and social participation. These associations were evaluated in the context of urban and non-urban geographic settings. METHODS: This study used data from the 2018 wave of the China Longitudinal Ageing Social Survey (N = 10,126), examining samples of urban (n = 3,917) and non-urban (n = 6,209) older adults separately. Linear regression and path analysis within a structural equation modeling framework were employed. RESULTS: Internet use was negatively associated with loneliness for both urban and non-urban residing older adults. Family support and social participation mediated the association between internet use and loneliness for both urban and non-urban residing older Chinese adults, but friend support mediated this association only for urban older residents. DISCUSSION: This study shed light on our understanding of the relationship between internet use and loneliness among older adults in the Chinese context. Also, these findings suggested that digital interventions for loneliness should pay special attention to the different characteristics of urban and non-urban dwelling older Chinese adults.

In Situ Triggered Self-Contraction Bioactive Microgel Assembly Accelerates Diabetic Skin Wound Healing by Activating Mechanotransduction and Biochemical Pathway.

Chronic nonhealing skin wounds, characterized by reduced tissue contractility and inhibited wound cell survival under hyperglycemia and hypoxia, present a significant challenge in diabetic care. Here, an advanced self-contraction bioactive core-shell microgel assembly with robust tissue-adhesion (SMART-EXO) is introduced to expedite diabetic wound healing. The SMART-EXO dressing exhibits strong, reversible adhesion to damaged tissue due to abundant hydrogen and dynamic coordination bonds. Additionally, the core-shell microgel components and dynamic coordination bonds provide moderate rigidity, customizable self-contraction, and an interlinked porous architecture. The triggered in situ self-contraction of the SMART-EXO dressing enables active, tunable wound contraction, activating mechanotransduction in the skin and promoting the optimal fibroblast-to-myofibroblast conversion, collagen synthesis, and angiogenesis. Concurrently, the triggered contraction of SMART-EXO facilitates efficient loading and on-demand release of bioactive exosomes, contributing to re-epithelialization and wound microenvironment regulation in diabetic mice. RNA-seq results reveal the activation of critical signaling pathways associated with mechanosensing and exosome regulation, highlighting the combined biomechanical and biochemical mechanisms. These findings underscore SMART-EXO as a versatile, adaptable solution to the complex challenges of diabetic wound care.

Orientation-Dependent Mechanical Behaviors of BCC-Fe in Light of the Thermo-Kinetic Synergy of Plastic Deformation.

The orientation-dependent mechanical behaviors of metallic alloys are governed by deformation mechanisms, but the underlying physics remain to be explored. In this work, the mechanical responses along different orientations and behind the mechanisms of BCC-Fe are investigated by performing molecular dynamic simulations. It is found that the mechanical properties of BCC-Fe exhibit apparent anisotropic characteristics. The <100>-oriented BCC-Fe presents a Young's modulus of E = 147.56 GPa, a strength of σy = 10.15 GPa, and a plastic strain of εy = 0.084 at the yield point, whereas the <111> orientation presents E = 244.84 GPa, σy = 27.57 GPa, and εy = 0.21. Based on classical dislocation theory, the reasons for such orientation-dependent mechanical behaviors are analyzed from the perspective of thermo-kinetic synergy upon deformation. It turns out that the anisotropic mechanical responses of BCC-Fe are associated with the magnitude of the thermodynamic driving force (ΔG) and kinetic energy barrier (Q) for dislocation motion, which dominate the corresponding deformation mechanism. Compared with the low ΔG (6.395 GPa) and high Q (11.95 KJ/mol) of the <100>-oriented BCC-Fe dominated by deformation twinning, the <111> orientation governed by dislocation slip presents a high ΔG (17.37 GPa) and low Q (6.45 KJ/mol). Accordingly, the orientation-dependent deformation behaviors of BCC-Fe are derived from the thermo-kinetic synergy for dislocation motion.

Positive Association of Urinary Dimethylarsinic Acid (DMAV) with Serum 25(OH)D in Adults Living in an Area of Water-Borne Arsenicosis in Shanxi, China.

Limited studies have demonstrated that inorganic arsenic exposure is positively associated with serum vitamin D levels, although the correlation between urinary arsenic species and serum vitamin D has not been investigated in areas of water-borne arsenicosis. A cross-sectional study of 762 participants was conducted in Wenshui Country, Shanxi Province, a water-borne arsenicosis area. The results showed a positive relationship between urinary arsenic species (inorganic arsenic (iAs), methylarsonic acid (MMAV), dimethylarsinic acid (DMAV) and serum 25(OH)D. Log-binomial regression analysis indicated a 0.4% increase in the risk of vitamin D excess for every 1-unit increment in the Box-Cox transformed urinary DMAV after adjustment for covariates. After stratifying populations by inorganic arsenic methylation metabolic capacity, serum 25(OH)D levels in the populations with iAs% above the median and primary methylation index (PMI) below the median increased by 0.064 ng/mL (95% CI: 0.032 to 0.096) for every one-unit increase in the Box-Cox transformed total arsenic (tAs) levels. Serum 25(OH)D levels increased by 0.592 ng/mL (95% CI: 0.041 to 1.143) for every one-unit rise in the Box-Cox transformed iAs levels in people with skin hyperkeratosis. Overall, our findings support a positive relationship between urinary arsenic species and serum 25(OH)D. It was recommended that those residing in regions with water-borne arsenicosis should take moderate vitamin D supplements to avoid vitamin D poisoning.

Surface hydrophobization of hydrogels via interface dynamics-induced network reconfiguration.

Effective and easy regulation of hydrogel surface properties without changing the overall chemical composition is important for their diverse applications but remains challenging to achieve. We report a generalizable strategy to reconfigure hydrogel surface networks based on hydrogel-substrate interface dynamics for manipulation of hydrogel surface wettability and bioadhesion. We show that the grafting of hydrophobic yet flexible polymeric chains on mold substrates can significantly elevate the content of hydrophobic polymer backbones and reduce the presence of polar groups in hydrogel surface networks, thereby transforming the otherwise hydrophilic hydrogel surface into a hydrophobic surface. Experimental results show that the grafted highly dynamic hydrophobic chains achieved with optimal grafting density, chain length, and chain structure are critical for such substantial hydrogel surface network reconfiguration. Molecular dynamics simulations further reveal the atomistic details of the hydrogel network reconfiguration induced by the dynamic interface interactions. The hydrogels prepared using our strategy show substantially enhanced bioadhesion and transdermal delivery compared with the hydrogels of the same chemical composition but fabricated via the conventional method. Our findings provide important insights into the dynamic hydrogel-substrate interactions and are instrumental to the preparation of hydrogels with custom surface properties.

Photonic control of ligand nanospacing in self-assembly regulates stem cell fate.

Extracellular matrix (ECM) undergoes dynamic inflation that dynamically changes ligand nanospacing but has not been explored. Here we utilize ECM-mimicking photocontrolled supramolecular ligand-tunable Azo+ self-assembly composed of azobenzene derivatives (Azo+) stacked via cation-π interactions and stabilized with RGD ligand-bearing poly(acrylic acid). Near-infrared-upconverted-ultraviolet light induces cis-Azo+-mediated inflation that suppresses cation-π interactions, thereby inflating liganded self-assembly. This inflation increases nanospacing of "closely nanospaced" ligands from 1.8 nm to 2.6 nm and the surface area of liganded self-assembly that facilitate stem cell adhesion, mechanosensing, and differentiation both in vitro and in vivo, including the release of loaded molecules by destabilizing water bridges and hydrogen bonds between the Azo+ molecules and loaded molecules. Conversely, visible light induces trans-Azo+ formation that facilitates cation-π interactions, thereby deflating self-assembly with "closely nanospaced" ligands that inhibits stem cell adhesion, mechanosensing, and differentiation. In stark contrast, when ligand nanospacing increases from 8.7 nm to 12.2 nm via the inflation of self-assembly, the surface area of "distantly nanospaced" ligands increases, thereby suppressing stem cell adhesion, mechanosensing, and differentiation. Long-term in vivo stability of self-assembly via real-time tracking and upconversion are verified. This tuning of ligand nanospacing can unravel dynamic ligand-cell interactions for stem cell-regulated tissue regeneration.

Current Knowledge of Th22 Cell and IL-22 Functions in Infectious Diseases.

T helper 22 (Th22) cells, a newly defined CD4+ T-cell lineage, are characterized by their distinct cytokine profile, which primarily consists of IL-13, IL-22 and TNF-α. Th22 cells express a wide spectrum of chemokine receptors, such as CCR4, CCR6 and CCR10. The main effector molecule secreted by Th22 cells is IL-22, a member of the IL-10 family, which acts by binding to IL-22R and triggering a complex downstream signaling system. Th22 cells and IL-22 have been found to play variable roles in human immunity. In preventing the progression of infections such as HIV and influenza, Th22/IL-22 exhibited protective anti-inflammatory characteristics, and their deleterious proinflammatory activities have been demonstrated to exacerbate other illnesses, including hepatitis B and Helicobacter pylori infection. Herein, we review the current understanding of Th22 cells, including their definition, differentiation and mechanisms, and the effect of Th22/IL-22 on human infectious diseases. According to studies on Th22 cells, Th22/IL-22 may be a promising therapeutic target and an effective treatment strategy for various infections.

Online engagement, resilience, and loneliness among older people during the COVID-19 pandemic.

BACKGROUND AND OBJECTIVES: The COVID-19 pandemic exacerbated the public health concerns of social isolation and loneliness for older people who are vulnerable due to their health conditions and more restrictive social measures. However studies revealed that many older adults demonstrated high resilience and remained emotionally stable during the pandemic, particularly those who had a broad engagement with online technology that could compensate for their isolation. Yet, little empirical research has examined explicitly the association between online engagement and loneliness among older adults, and the role resilience played in this relationship during the pandemic. This study contributed to the literature by addressing these research gaps. RESEARCH DESIGN AND METHODS: This study investigated the relationships between online engagement (sum of involvement in 31 online activities), resilience (sum of positive experiences and personal growth during COVID-19) and loneliness (mean of 11-items from the revised version of the UCLA loneliness scale) among community-dwelling older people (aged 60+), using national survey data from the 2020 Health and Retirement Study (HRS) collected during the COVID-19 pandemic (N = 3,552). RESULTS AND CONCLUSION: Online engagement was negatively associated with levels of loneliness (ß = -0.080, 95% CI [-0.118, -0.047]), and this association was partially mediated by levels of resilience (ß = -0.023, 95% CI [-0.031, -0.016]. The findings suggested that a broad integration of online technology into daily-life may have helped older people combat loneliness during the pandemic, and resilience could be one important mechanism that linked this association.

Mechanical manipulation of cancer cell tumorigenicity via heat shock protein signaling.

Biophysical cues of rigid tumor matrix play a critical role in cancer cell malignancy. We report that stiffly confined cancer cells exhibit robust growth of spheroids in the stiff hydrogel that exerts substantial confining stress on the cells. The stressed condition activated Hsp (heat shock protein)-signal transducer and activator of transcription 3 signaling via the transient receptor potential vanilloid 4-phosphatidylinositol 3-kinase/Akt axis, thereby up-regulating the expression of the stemness-related markers in cancer cells, whereas these signaling activities were suppressed in cancer cells cultured in softer hydrogels or stiff hydrogels with stress relief or Hsp70 knockdown/inhibition. This mechanopriming based on three-dimensional culture enhanced cancer cell tumorigenicity and metastasis in animal models upon transplantation, and pharmaceutically inhibiting Hsp70 improved the anticancer efficacy of chemotherapy. Mechanistically, our study reveals the crucial role of Hsp70 in regulating cancer cell malignancy under mechanically stressed conditions and its impacts on cancer prognosis-related molecular pathways for cancer treatments.