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Chirality, a fundamental design feature at all levels of life organization, has shown great capability in guiding cell‐fate determination and tissue regeneration. Chirality‐directed differentiation programs involve remarkable changes in transcriptional networks, yet whether epigenetic regulatory events are also required is less well understood. Herein, by combining high‐throughput m6A MeRIP sequencing, RIP‐qPCR, and gene modulation techniques, it is demonstrated that biomimetic chiral nanofibrils can bidirectionally regulate wilms tumor 1 associated protein (WTAP)‐mediated m6A RNA methylation to guide macrophages polarization for tissue regeneration. The biomimic chiral nanofibril hydrogels are fabricated using a self‐assembly approach based on C2‐symmetric phenylalanine derivatives. In vitro and in vivo studies indicated that the L‐nanofibrils exhibit a greater propensity to promote M2‐macrophage polarization than D‐nanofibrils, thereby favoring osteogenesis. Then, m6A‐MeRIP sequencing revealed a unique chirality‐dependent m6A methylation level in macrophages, which was gated by a competitive pair of CCM3‐FAK through enantioselectively integrin recognition. L‐nanofibrils considerably suppressed WTAP‐mediated m6A methylation by promoting Itgα3‐FAK expression and paxillin‐driven mechanotransduction, whereas D‐nanofibrils induced WTAP‐mediated m6A methylation by favoring ItgαV‐CCM3 expression and suppressing mechanotransduction. Furthermore, the gain‐of‐function and loss‐of‐function experiments and RIP‐qPCR demonstrate that the WTAP expression could direct macrophage polarization via manipulating the functional molecule B7‐H3 (CD276). Thus, a mechano‐epigenetic mechanism of chirality‐mediated cell‐fate determination is unveiled, which holds remarkable promise in the realm of assisted regenerative material design. [ABSTRACT FROM AUTHOR]

Hypoxic injury poses a severe threat to cell survival. Activation of pro‐survival autophagy via autophagy‐inducing nanomaterials (AINMs) has emerged as one of the most promising therapeutic strategies. However, internalized AINMs easily bind with intracellular lysosomes, resulting in disruptive effects on autophagic flux and limited pro‐survival effects. Herein, inspired by the naturally existing chiral structures in actin membrane protein, two nanofibers based on achiral pyridine‐substituted coumarin derivatives (PyC) with only difference in supramolecular chirality are constructed by the method of chirality memory to activate autophagy extracellularly. The high degree of conformational chirality matching between right‐handed PyC‐r nanofibers and actin ensures an enhanced stereoselective interaction between the pyridine groups on PyC and the hydroxyl groups on serine‐rich Girdin protein (an actin‐binding protein involved in cell survival). This stereoselective interaction can activate the autophagy‐related Akt/mTOR pathway via mechanical signal transmission and phosphorylation of Akt, which avoids the disruption of autophagic flux and significantly mitigates cellular hypoxic injury. In a rat myocardial ischemia model, scar formation and functional deterioration are particularly alleviated by injection of PyC‐r nanofibers into murine infarcted myocardium. The findings pioneeringly establish a direct link between chiral biomedical materials and cellular autophagy, offering novel insights for cellular hypoxic protection. [ABSTRACT FROM AUTHOR]

Sodium aescinate (SA) shows great potential for treating lymphedema since it can regulate the expression of cytokines in M1 macrophages, however, it is commonly administered intravenously in clinical practice and often accompanied by severe toxic side effects and short metabolic cycles. Herein, SA‐loaded chiral supramolecular hydrogels are prepared to prove the curative effects of SA on lymphedema and enhance its safety and transdermal transmission efficiency. In vitro studies demonstrate that SA‐ loaded chiral supramolecular hydrogels can modulate local immune responses by inhibiting M1 macrophage polarization. Typically, these chiral hydrogels can significantly increase the permeability of SA with good biocompatibility due to the high enantioselectivity between chiral gelators and stratum corneum and L‐type hydrogels are found to have preferable drug penetration over D‐type hydrogels. In vivo studies show that topical delivery of SA via chiral hydrogels results in dramatic therapeutic effects on lymphedema. Specifically, it can downregulate the level of inflammatory cytokines, reduce the development of fibrosis, and promote the regeneration of lymphatic vessels. This study initiates the use of SA for lymphedema treatment and for the creation of an effective chiral biological platform for improved topical administration. [ABSTRACT FROM AUTHOR]

To comprehend the significance of improved conductive properties in C2‐symmetric hydrogels, it is vital to investigate how non‐gelating achiral functional group isomers influence the conductivity of such supramolecular hydrogels, whereas understanding the major driving forces behind this regulatory process is first and foremost. Herein, we report a hydrogel system containing tryptophan‐conjugated NDI as the backbone (L/D‐NTrp), enabling effective supramolecular assembly with the bipyridyl functional group isomers. This co‐assembly behavior results in materials with exceptional mechanical properties and high conductivities, surpassing most previously reported C2‐symmetrical hydrogels, as well as the ability to form controlled morphologies. Notably, the co‐hydrogels displayed an eight‐fold increase in mechanical strength, making them more robust and resistant to deformation compared to the original gel. Additionally, all hydrogels exhibited favorable electrical conductivity, with the co‐assembled hydrogels showcasing notable performance, making them a promising candidate for use in electronic devices and sensors. This report lays the foundation for further investigation into the properties and potential applications of L/D‐NTrp compound in the range of fields, including drug delivery, tissue engineering, and electronics. [ABSTRACT FROM AUTHOR]

Chiral supramolecular assemblies with helical structures (e. g. proteins with α‐helix, DNA with double helix, collagen with triple‐helix) as the central structure motifs in biological systems play a crucial role in various physiological activities of living organisms. Variations in chiral structure can cause many abnormal physiological activities. To gain insight into the construction, structural transition, and related physiological functions of these complex helix in natural systems, it is necessary to fabricate artificial supramolecular assemblies with controllable helix orientation as research platform. This review discusses recent advances in chiral supramolecular assembly, including the precise construction and regulation of assembled chiral nanostructures with tunable chirality. Chiral structure‐dependent biological activities, including cell proliferation, cell differentiation, antibacterial activity and tissue regeneration, are also discussed. This review not only contributes to further understanding of the importance of chirality in the physiological environment, but also plays an important role in the development of chiral biomedical materials for the treatment of diseases (e. g. tissue engineering regeneration, stem cell transplantation therapy). [ABSTRACT FROM AUTHOR]

The induction of diverse chirality regulation in nature by multiple binding sites of biomolecules is ubiquitous and plays an essential role in determining the biofunction of biosystems. However, mimicking this biological phenomenon and understanding at a molecular level its mechanism with the multiple binding sites by establishing an artificial system still remains a challenge. Herein, abundant chirality inversion is achieved by precisely and multiply manipulating the co‐assembled binding sites of phenylalanine derivatives (D/LPPF) with different naphthalene derivatives (NA, NC, NP, NF). The amide and hydroxy group of naphthalene derivatives prefer to bind with the carboxy group of LPPF, while carboxylic groups and fluoride atoms tend to bind with the amide moiety of LPPF. All these diverse interaction modes can precisely trigger helicity inversion of LPPF nanofibers. In addition, synergistically manipulating the carboxy and amide binding sites from a single LPPF molecule to simultaneously interact with different naphthalene derivatives leads to chirality regulation. Typically, varying the solvent may switch the interaction modes and the switched new interaction modes can be employed to further regulate the chirality of the LPPF nanofibers. This study may provide a novel approach to explore chirality diversity in artificial systems by regulating the intermolecular binding sites. [ABSTRACT FROM AUTHOR]