Synthetic fibrous hydrogels as a platform to decipher cell-matrix mechanical interactions.

Cells continuously sense external forces from their microenvironment, the extracellular matrix (ECM). In turn, they generate contractile forces, which stiffen and remodel this matrix. Although this bidirectional mechanical exchange is crucial for many cell functions, it remains poorly understood. Key challenges are that the majority of available matrices for such studies, either natural or synthetic, are difficult to control or lack biological relevance. Here, we use a synthetic, yet highly biomimetic hydrogel based on polyisocyanide (PIC) polymers to investigate the effects of the fibrous architecture and the nonlinear mechanics on cell-matrix interactions. Live-cell rheology was combined with advanced microscopy-based approaches to understand the mechanisms behind cell-induced matrix stiffening and plastic remodeling. We demonstrate how cell-mediated fiber remodeling and the propagation of fiber displacements are modulated by adjusting the biological and mechanical properties of this material. Moreover, we validate the biological relevance of our results by demonstrating that cellular tractions in PIC gels develop analogously to those in the natural ECM. This study highlights the potential of PIC gels to disentangle complex bidirectional cell-matrix interactions and to improve the design of materials for mechanobiology studies.

Microenvironment with NIR-Controlled ROS and Mechanical Tensions for Manipulating Cell Activities in Wound Healing.

The extracellular matrix (ECM) orchestrates cell behavior and tissue regeneration by modulating biochemical and mechanical signals. Manipulating cell-material interactions is crucial for leveraging biomaterials to regulate cell functions. Yet, integrating multiple cues in a single material remains a challenge. Here, near-infrared (NIR)-controlled multifunctional hydrogel platforms, named PIC/CM@NPs, are introduced to dictate fibroblast behavior during wound healing by tuning the matrix oxidative stress and mechanical tensions. PIC/CM@NPs are prepared through cell adhesion-medicated assembly of collagen-like polyisocyanide (PIC) polymers and cell-membrane-coated conjugated polymer nanoparticles (CM@NPs), which closely mimic the fibrous structure and nonlinear mechanics of ECM. Upon NIR stimulation, PIC/CM@NPs composites enhance fibroblast cell proliferation, migration, cytokine production, and myofibroblast activation, crucial for wound closure. Moreover, they exhibit effective and toxin removal antibacterial properties, reducing inflammation. This multifunctional approach accelerates healing by 95%, highlighting the importance of integrating biochemical and biophysical cues in the biomaterial design for advanced tissue regeneration.

A Strategy of On-Demand Immune Activation for Antifungal Treatment Using Near-Infrared Responsive Conjugated Polymer Nanoparticles.

Pathogenic fungal infection is a major clinical threat because pathogenic fungi have developed resistant mechanisms to evade the innate immune response, especially interactions with macrophages. Herein, a strategy to activate immune responses of macrophages to fungi based on near-infrared (NIR) responsive conjugated polymer nanoparticles (CPNs-M) is reported for antifungal immunotherapy. Under NIR light irradiation, CPNs-M exposes ß-glucan on the surface of fungal conidia by photothermal damage and drug released from CPNs-M. The exposed ß-glucan elicits macrophage recognition and subsequently activates calcium-calmodulin (Ca2+-CaM) signaling followed by the LC3-associated phagocytosis (LAP) pathway to kill fungal conidia. Consequently, a remarkable elimination of intracellular fugal conidia and successful treatment of fungal pneumonia are achieved. This remote regulation strategy to restore pathogen-immune cell interaction on demand provides a new insight into combatting intractable intracellular infections.

Dual Activation of Calcium Channels Using Near-Infrared Responsive Conjugated Oligomer Nanoparticles for Precise Regulation of Blood Glucose Homeostasis.

The rarity of efficient tools with spatiotemporal resolution and biocompatibility capabilities remains a major challenge for further progress and application of signaling manipulation. Herein, biomimetic conjugated oligomeric nanoparticles (CM-CONs) were developed to precisely modulate blood glucose homeostasis via the two-pronged activation of calcium channels. Under near-infrared (NIR) laser irradiation, CM-CONs efficiently generate local heat and reactive oxygen species (ROS), thereby simultaneously activating thermosensitive transient receptor potential V1 (TRPV1) and ROS-sensitive transient receptor potential A1 (TRPA1) calcium channels in small intestinal endocrine cells. The activation of the channels mediates inward calcium flow and then promotes glucagon-like peptide (GLP-1) secretion. Both in vitro and in vivo studies indicate that CM-CONs effectively regulate glucose homeostasis in diabetic model mice upon NIR light irradiation. This work develops a two-pronged attack strategy for accurately controlling blood glucose homeostasis, holding great prospects in the treatment for diabetes.

Polymerization-Induced Self-Assembly: An Emerging Tool for Generating Polymer-Based Biohybrid Nanostructures.

The combination of biomolecules and synthetic polymers provides an easy access to utilize advantages from both the synthetic world and nature. This is not only important for the development of novel innovative materials, but also promotes the application of biomolecules in various fields including medicine, catalysis, and water treatment, etc. Due to the rapid progress in synthesis strategies for polymer nanomaterials and deepened understanding of biomolecules' structures and functions, the construction of advanced polymer-based biohybrid nanostructures (PBBNs) becomes prospective and attainable. Polymerization-induced self-assembly (PISA), as an efficient and versatile technique in obtaining polymeric nano-objects at high concentrations, has demonstrated to be an attractive alternative to existing self-assembly procedures. Those advantages induce the focus on the fabrication of PBBNs via the PISA technique. In this review, current preparation strategies are illustrated based on the PISA technique for achieving various PBBNs, including grafting-from and grafting-through methods, as well as encapsulation of biomolecules during and subsequent to the PISA process. Finally, advantages and drawbacks are discussed in the fabrication of PBBNs via the PISA technique and obstacles are identified that need to be overcome to enable commercial application.

Remote Manipulation of ROS-Sensitive Calcium Channel Using Near-Infrared-Responsive Conjugated Oligomer Nanoparticles for Enhanced Tumor Therapy In Vivo.

The regulation of reactive oxygen species (ROS)-sensitive calcium (Ca2+) channels is of great significance in the treatment of tumors. Here, a simple ROS generation system is developed to activate ROS-sensitive ion channels for enhancing calcium-cascade-mediated tumor cell death under near-infrared (NIR) light irradiation. Upon irradiation with an 808 nm laser, a low-lethality amount of ROS facilitates plasmid transient potential receptor melastatin-2 (pTRPM2) gene release via cleavage of the Se-Se bonds, which contributed to enhancing the expression of TRPM2 in tumor cells. Meanwhile, ROS could potently activate TRPM2 for Ca2+ influx to inhibit early autophagy and to further induce intracellular ROS production, which ultimately led to cell death in TRPM2 expressing tumor cells. Both in vitro and in vivo data show that nanoparticles have an excellent therapeutic effect on cancer upon NIR light. This work presents a simple modality based on NIR light to remotely control the ROS-sensitive ion channel for cancer therapy.

The Preparation of Biomineralized PIC/HA Hybrid Composites with Strain-Stiffening and the Effect on MC3T3-E1 Cells.

The development of biomimetic extracellular matrix (ECM) with fibrous structure and complex nonlinear mechanics has been attracting intensive attention over the past decades both in material science and tissue engineering. Polyisocyanopeptide (PIC) hydrogels are a class of fully synthetic materials that can mimic biogels, such as fibrin and collagen, in nearly all aspects, particularly the micron-sized gel network and the strong strain-stiffening behavior in the biological regime. Here, a biomimetic PIC/hydroxyapatite (HA) hybrid composite through an enzymatic biomineralization strategy is constructed. HA biominerals grew on PIC bundles in situ catalyzed by the embedded alkaline phosphatase (ALP), which further crosslinked the gel networks and reinforced the mechanical property of PIC hydrogels. Significantly, PIC/HA composites exhibited ultra-responsive nonlinear mechanics with higher sensitivity to mechanical stress compared with those without biomineralization. As a consequence, the presence of HA can provide cell adhesion sites for PIC gels and induce osteogenic differentiation of pre-osteoblasts by virtue of the changes in mechanical properties. With these outstanding properties, therefore, PIC/HA composites present promising prospects in bone tissue engineering as biomimetic ECM.

Construction of Highly Ordered Glyco-Inside Nano-Assemblies through RAFT Dispersion Polymerization of Galactose-Decorated Monomer.

Glyco-assemblies derived from amphiphilic sugar-decorated block copolymers (ASBCs) have emerged prominently due to their wide application, for example, in biomedicine and as drug carriers. However, to efficiently construct these glyco-assemblies is still a challenge. Herein, we report an efficient technology for the synthesis of glyco-inside nano-assemblies by utilizing RAFT polymerization of a galactose-decorated methacrylate for polymerization-induced self-assembly (PISA). Using this approach, a series of highly ordered glyco-inside nano-assemblies containing intermediate morphologies were fabricated by adjusting the length of the hydrophobic glycoblock and the polymerization solids content. A specific morphology of complex vesicles was captured during the PISA process and the formation mechanism is explained by the morphology of its precursor and intermediate. Thus, this method establishes a powerful route to fabricate glyco-assemblies with tunable morphologies and variable sizes, which is significant to enable the large-scale fabrication and wide application of glyco-assemblies.

Biomimetic Networks with Enhanced Photodynamic Antimicrobial Activity from Conjugated Polythiophene/Polyisocyanide Hybrid Hydrogels.

Hybrid biomimetic hydrogels with enhanced reactive oxygen species (ROS)-generation efficiency under 600 nm light show high antibacterial activity. The hybrid gels are composed of helical tri(ethylene glycol)-functionalized polyisocyanides (PICs) and a conformation-sensitive conjugated polythiophene, poly(3-(3'-N,N,N-triethylammonium-1'-propyloxy)-4-methyl-2,5-thiophene chloride) (PMNT). The PIC polymer serves as a scaffold to trap and align the PMNT backbone into a highly ordered conformation, resulting in redshifted, new sharp bands in the absorption and fluorescence spectra. Similar to PIC, the hybrid closely mimics the mechanical properties of biological gels, such as collagen and fibrin, including the strain stiffening properties at low stresses. Moreover, the PMNT/PIC hybrids show much higher ROS production efficiency under red light than PMNT only, leading to an efficient photodynamic antimicrobial effect towards various pathogenic bacteria.

Hydrocinnamic Acid Inhibits the Currents of WT and SQT3 Syndrome-Related Mutants of Kir2.1 Channel.

Gain of function in mutations, D172N and E299V, of Kir2.1 will induce type III short QT syndrome. In our previous work, we had identified that a mixture of traditional Chinese medicine, styrax, is a blocker of Kir2.1. Here, we determined a monomer, hydrocinnamic acid (HA), as the effective component from 18 compounds of styrax. Our data show that HA can inhibit the currents of Kir2.1 channel in both excised inside-out and whole-cell patch with the IC50 of 5.21 ± 1.02 and 10.08 ± 0.46 mM, respectively. The time course of HA blockage and washout are 2.3 ± 0.6 and 10.5 ± 2.6 s in the excised inside-out patch. Moreover, HA can also abolish the currents of D172N and E299V with the IC50 of 6.66 ± 0.57 and 5.81 ± 1.10 mM for D172N and E299V, respectively. Molecular docking results determine that HA binds with Kir2.1 at K182, K185, and K188, which are phosphatidylinositol 4,5-bisphosphate (PIP2) binding residues. Our results indicate that HA competes with PIP2 to bind with Kir2.1 and inhibits the currents.

Carbon Dioxide-Controlled Assembly of Water-Soluble Conjugated Polymers Catalyzed by Carbonic Anhydrase.

The CO2 -responsive and biocatalytic assembly based on conjugated polymers has been demonstrated by combining the signal amplification property of the polythiophene derivative (PTP) and the catalytic actions of carbonic anhydrase (CA). CO2 is applied as a new trigger mode to construct the smart assembly by controlling the electrostatic and hydrophobic interactions between the PTP molecules in aqueous solution, leading to the visible fluorescence changes. Importantly, the assembly transformation of PTP can be specifically and highly accelerated by CA based on the efficient catalytic activity of CA for the inter-conversion between CO2 and HCO3- , mimicking the CO2 -associated biological processes that occurred naturally in living organisms. Moreover, the PTP-based assembly can be applied for biomimetic CO2 sequestration with fluorescence monitoring in the presence of CA and calcium.

Conjugated Polymer-Based Hybrid Materials for Turn-On Detection of CO2 in Plant Photosynthesis.

Detection of carbon dioxide (CO2) is of fundamental importance in diverse applications ranging from environmental analysis to agricultural production. In this work, a hybrid probe based on guanidinium-pendent oligofluorene (G-OF) and water-soluble conjugated polythiophene (PTP) has been developed for the turn on detection of CO2 with low background signal, taking advantage of the efficient fluorescence quenching of the tight aggregate of G-OF/PTP. In the presence of CO2, the electrostatic repulsion between G-OF and PTP can be effectively enhanced through protonation of the side chains, leading to the disaggregation and thus the "turn-on" fluorescence. The strategy allows for the light-up visible detection of CO2 with high sensitivity. Importantly, this system is capable of sensitively monitoring the concentration changes of CO2 in the process of the photosynthesis, which represents a concept to monitor the photosynthesis based on water-soluble conjugated polymers.

Design Strategy of Microneedle Systems for Skin Wound Healing: Based on the Structure of Tips and Therapeutic Methodologies.

The skin, being the largest organ of the human body, is susceptible to damage resulting in wounds that are vulnerable to pathogenic attacks and fail to provide effective protection for internal tissues. Therefore, it is crucial to expedite wound healing. In recent years, microneedles have garnered significant attention as an innovative drug delivery system owing to their noninvasive and painless administration, simplified application process, precise control over drug release, and versatile loading capabilities. Consequently, they hold immense potential for the treatment of skin wound. This review presents a comprehensive design strategy for the microneedle system in promoting skin wound healing. First, the process of skin wound healing and the characteristics of specific wounds are elucidated. The design strategies for microneedles are subsequently presented and classified based on their structural and therapeutic methodologies. Finally, a succinct recapitulation of the previously discussed points and a prospective analysis are provided.

A Stepwise Targeting and Antibacterial Strategy by Leukocyte Membrane-Based Conjugated Oligomer Nanoparticles.

Bacterial infection poses an enormous threat to human life and health. The inability of drugs to be effectively delivered to the site of infection and the development of bacterial resistance make the treatment process more difficult. Herein, a stepwise targeted biomimetic nanoparticle (NPs@M-P) with inflammatory tendency and Gram-negative bacterial targeting was designed, which can achieve efficient antibacterial activity under near-infrared triggering. Leukocyte membranes and targeted molecules (PMB) are used to deliver NPs to the surface of Gram-negative bacteria. The heat and ROS released by NPs@M-P can efficiently kill Gram-negative bacteria under low-power near-infrared light. Thus, this multimodal combination therapy strategy has broad promise in fighting bacterial infection and avoiding drug resistance.

NIR-II Regulation of Mitochondrial Potassium Channel with Dual-Targeted Conjugated Oligomer Nanoparticles for Efficient Cancer Theranostics In Vivo.

Cell fate can be efficiently modulated by switching ion channels. However, the precise regulation of ion channels in cells, especially in specific organelles, remains challenging. Herein, biomimetic second near-infrared (NIR-II) responsive conjugated oligomer nanoparticles with dual-targeted properties are designed and prepared to modulate the ion channels of mitochondria to selectively kill malignant cells in vivo. Upon 1060 nm laser irradiation, the mitochondria-located nanoparticles photothermally release a specific ion inhibitor of the potassium channel via a temperature-sensitive liposome, thus altering the redox balance and pathways of mitochondria. NIR-II responsive nanoparticles can effectively regulate the potassium channels of mitochondria and fully suppress tumor growth. This work provides a new modality based on the NIR-II nanoplatform to regulate ion channels in specific organelles and proposes an effective therapeutic mechanism for malignant tumors.

Conjugated polymers for light-activated antifungal activity.

A cationic polythiophene-porphyrin (PTP) dyad is shown to exhibit efficient light-activated antifungal activity. Higher singlet oxygen (¹O2) generation efficiency can be attained from PTP upon photoexcitation due to the light-harvesting properties of the polymer backbone and efficient energy transfer from the polythiophene to the porphyrin units. PTP can be used for treating fungal infections in lower doses of irradiation light and polymer concentration.

Regulation of Ca2+ for Cancer Cell Apoptosis through Photothermal Conjugated Nanoparticles.

Ca2+ overload is caused by the abnormal accumulation of Ca2+, which is a potential therapeutic strategy for inhibiting tumor growth. However, due to the limited intracellular Ca2+ concentration, its anticancer effect is non-significant. Herein, near-infrared (NIR)-responsive nanoparticles NPs-PCa (DPPC-DSPE-PEG2000-NH2@PDPP@CaO2@DOX) were designed and prepared to achieve photothermal trigger of Ca2+ release, thereby increasing intracellular Ca2+ content. Furthermore, the nanoparticles convert light to heat to activate the transient receptor potential cation channel subfamily V member 1 (TRPV1) ion channels, allowing external Ca2+ to flow into the cells, further increasing the Ca2+ concentration. NPs-PCa nanoparticles overcome the limitation of insufficient concentration by increasing Ca2+ in both internal and external approaches. Meanwhile, an imbalance of intracellular Ca2+ induces mitochondrial dysfunction and ultimately results in cancer cell death. This study provides an effective strategy for inhibiting breast cancer tumor growth by regulating Ca2+ concentration.

Mild-Temperature Photothermal Effect Enhanced by Functional Conjugated Polymer Nanoparticles through Enzyme-Mediated Starvation.

Mild-temperature photothermal therapy (PTT) is being extensively explored because it causes less injury to normal cells. However, the effect of mild-temperature PTT is decreased because of heat shock protein (HSP) overexpression. To solve this problem, we designed functional conjugated polymer nanoparticles (CPNs-G) that enhance the mild-temperature photothermal effect. Upon near-infrared (NIR) light irradiation, CPNs-G generate local heat to realize the photothermal effect. Meanwhile, the increased temperature enhances the catalytic activity of GOx, thus impeding the generation of adenosine triphosphate (ATP) and inhibiting HSP expression. Therefore, this work provides a strategy for overcoming thermoresistance through an enzyme-mediated starvation effect regulated by NIR light.

Near-Infrared Light-Responsive Nanoinhibitors for Tumor Suppression through Targeting and Regulating Anion Channels.

The gated state of anion channels is involved in the regulation of proliferation and migration of tumors. Specific regulators are urgently needed for efficacious cancer ablation. For this purpose, it is essential to understand the molecular mechanisms of interaction between the regulators and anion channels and apply this knowledge to regulate anion channels. Transmembrane 16A (TMEM16A) is the molecular basis of the calcium-activated chloride channels. It is an anion channel activated by Ca2+, and the inhibition of TMEM16A is associated with a decrease in tumorigenesis. Herein, we characterized a natural compound procyanidin (PC) as an efficacious and selective inhibitor of TMEM16A with an IC50 of 10.6 ± 0.6 µM. Our research revealed the precise sites (D383, R535, and E624) of electrostatic interactions between PC and TMEM16A. Near-infrared (NIR)-light-responsive photothermal conjugated polymer nanoparticles encapsulating PC (CPNs-PC) were established to remotely target and regulate the TMEM16A anion channel. Upon NIR irradiation, CPNs-PC downregulated the signaling pathway downstream of TMEM16A and arrested the cell cycle progression of cancer cells and improved the bioavailability of PC. The tumor inhibition ratio of CPNs-PC was superior to PC by 13.4%. Our findings enabled the development of a strategy to accurately and remotely regulate anion channels to promote tumor regression using NIR-light-responsive conjugated polymer nanoparticles containing specific inhibitors of TMEM16A.

Photothermal Conjugated Polymer Nanoparticles for Suppressing Breast Tumor Growth by Regulating TRPA1 Ion Channels.

Cancer cells survive by relying on oxidative stress defense against the accumulation of reactive oxygen species (ROS) during tumor formation. ROS-sensitive TRPA1 ion channels are overexpressed in breast cancer cells and induce a large influx of Ca2+ which upregulates the anti-apoptotic pathway to lead breast cancer cells to produce oxidative stress defense and enhance the resistance to ROS related chemotherapy. Targeting and inhibiting the TRPA1 ion channels are critical for breaking down the oxidative stress defense system and overcoming cellular resistance. Here, near-infrared (NIR) light-responsive conjugated polymer nanoparticles are designed and prepared to promote apoptosis of breast cancer cells, reduce cell drug resistance and suppress tumor growth through the remote and precise regulation of TRPA1 ion channels. Upon 808 nm laser irradiation, the nanoparticles block the formation of Ca2+ /CaM complex and regulate the content of MCL-1 protein. Especially, the nanoparticles overcome drug resistance of cancer cells, therefore accelerating apoptosis of cancer cells and suppressing tumor growth in mice. Compared with carboplatin, the volume of tumor induced by NPs-H decreases by 54.1%. This work provides a strategy to disrupt the oxidative stress defense system and downregulate the antiapoptotic signaling pathway in cancer cells.