Guosong Chen

Structural polysaccharides self-assemble into densely packed fibrils, providing a molecular foundation for the hierarchical organization and mechanical integrity of biological materials. However, the same interchain interactions that stabilize these structures severely restrict chemical accessibility, making molecular editing after assembly a formidable challenge. Here, we integrate regiochemical editing into bacterial cellulose biosynthesis using azido-glucose analogues substituted at C2, C3, or C6. The resulting cellulose materials exhibit regioisomer-dependent differences in crystallinity, fibrillar organization, and mechanical properties, while precursor feeding further modulates crystallinity. The incorporated azide groups remain chemically accessible after assembly, enabling DNA conjugation and rolling-circle amplification to construct sequence-programmable aptamer interfaces. By varying the aptamer sequence, the same cellulose platform can be reprogrammed for either selective cell capture and release or HGF-mimetic regulation of endothelial behavior. This work establishes a biosynthesis-integrated strategy that connects molecular editing during cellulose formation with hierarchical material organization and subsequent biological programming.

Stem cell-based therapy holds great promise for treating Parkinson's disease (PD), yet its clinical translation depends on safely and efficiently generating midbrain dopaminergic cells (mDACs) in vitro. One major challenge in current protocols is the safety risks associated with extracellular matrix (ECM) components. Commonly used materials such as laminin may contain undefined animal-derived components, while their human recombinant alternatives face technical and economic limitations, highlighting an urgent need for safe and effective materials for scalable clinical-grade cell manufacturing. Sialic acid is recognized as a crucial nutrient during neural development and a key structural component of brain sialylglycopeptide and gangliosides, but its use to optimize in vitro neuronal differentiation protocols has not been assessed. In this study, starting from the observation that sialyllactose supports mDAC differentiation, we identified a series of sialyl-glycopeptides as candidate matrix materials and comparatively evaluated their supramolecular morphology, nanomechanical flexibility, and matrix-supporting performance. Among these candidates, SL-4F, replacing laminin, combined with poly-l-ornithine and fibronectin, promotes robust mDAC growth and differentiation. The efficacy and safety of this formulation are confirmed in vitro and in vivo, suggesting SL-4F as a synthetic and safer alternative for clinical-grade cell culture for PD and, potentially, other stem cell-based therapies.

Despite the crucial roles of glycan structures in glycosylated macromolecules such as proteoglycans in the extracellular matrix, their regulatory mechanism is still poorly understood, due to the complex structures and dynamic interactions of polysaccharides. Here, supramolecular polymers were employed as simplified mimics for fibrous proteoglycans to investigate the regulatory role of the glycans. We constructed a series of glycopeptides based on the precise linear tetrasaccharide structure (CT) from chondroitin. Experimental and computational results indicated that glycopeptides containing triphenylalanine and chondroitin tetrasaccharide (CT-3F) could assemble into tetra-stranded nonhelical fibers. Compared with the glycopeptide fiber of nonlinear sialyllactose (SL-3F), the linear geometry of CT resulted in fewer hydrogen bonds than nonlinear SL, and consequently different flexibility of the corresponding supramolecular glycopolymers which was supported by the change of measured persistence length and bending modulus. Importantly, flexibility of CT-3F fibers from glycan geometry could significantly enhance their interaction with preosteoblastic cells and osteogenic gene expression. These results reveal an unexplored dimension of complex oligosaccharides and provide an alternative pathway for tuning the properties of supramolecular polymers and even related biomaterials.

Neoantigens are promising candidates for personalized cancer vaccines and immunotherapies. However, low immunogenicity and insufficient cross-presentation of neoantigens remain a major challenge. Inspired by natural glycocalyx and its important functions in immune response, here we report a glycocalyx-mimicking nanovehicle constructed from (oligo)mannoside-modified acid-sensitive glycopolymers to improve the efficiency of tumor neoantigens. These amphiphilic glycopolymers assembled into nanoparticles could serve as immune activators for dendritic cells maturation. The encapsulation of neoantigens in the glycopolymer nanocarrier improves the physicochemical properties and endosomal escape of the antigens, thereby not only enhancing their uptake and cross-presentation by dendritic cells but also promoting cytotoxic T cell proliferation and proinflammatory cytokine secretion. These results indicated that the glycocalyx-mimicking nanovehicle integrating delivery and immune adjuvant functions provides a promising platform for cancer vaccines.

The precise and complex immune activation of biomaterials has been the focus of intensive development and research in the fields of immunotherapy and vaccines. The structural diversity and programmability of biomacromolecules allow them to form highly effective platforms for activating immune responses and modulating multiple processes of immunogenicity. Therefore, many excellent approaches have been developed, leading to a variety of quite practical outcomes. This perspective highlights recent advances in using proteins and carbohydrates, important components involved in immune responses, as building blocks to create artificial biomaterials for immune activation. It summarizes how the structural properties of these biomaterials, ranging from molecular structures to mesoscopic structures, impact their uptake by immune cells and subsequent immune responses. Specifically, the effects of size, shape, and surface structures on inflammatory activation and T cell activation are discussed, followed by insights into their design for immunological applications.

Tumor progression is intricately associated with dysregulated extracellular matrix (ECM) remodeling. Supramolecular fibers composed of biomolecules exhibit structural and functional characteristics reminiscent of the native ECM. Leveraging this similarity, the construction of such fibers within the pericellular space may reconstruct the dysregulated ECM and act as a promising anticancer strategy, by remodeling the interactions between tumor cells and their microenvironment. In this study, we systematically evaluated a series of self-assembled glycopeptide fibers for their ability to inhibit tumor cell proliferation and angiogenesis. A truncated glycopeptide fiber demonstrated significantly enhanced efficacy in modulating the tumor microenvironment compared to other variants. Preliminary mechanistic investigations were also conducted, which revealed that the anti-tumor effect may be attributed to the physical interaction between fibers and tumor cells, thereby providing valuable insights into the mode of action. These findings not only highlight the therapeutic potential of glycopeptide-based fibrils but also pave the way for innovative approaches in cancer treatment.

Adoptive cell transfer has emerged as a promising approach for cancer immunotherapy. However, the transfer of macrophages is limited by their high plasticity, which can switch the pro-inflammatory phenotype (M1-like) to the anti-inflammatory state (M2-like) in an immunosuppressive microenvironment. Inspired by natural glycocalyx and its indispensable functions on immune response and communication, here we report an approach of hybrid glycocalyx-inspired nanoparticles that integrates (oligo)mannoside-modified glycopolymers with iron oxide to program primary macrophages into a persistent M1-like phenotype in which glycocalyx-inspired nanoparticles and iron oxide act as the extracellular and intracellular stimulatory signals, respectively. Importantly, with the synergistically enhanced immunoactivation of dual signals, the programmed macrophages are able to resist the immunosuppressive microenvironment and exhibit significantly enhanced tumoricidal effects both in vitro and in vivo. We further demonstrate that adoptive transfer of macrophages programmed by hybrid glycocalyx-inspired nanoparticles also improves the tumor microenvironment and increases T cell responses. These results, using glycocalyx mimetics as macrophage encoders, highlight an alternative approach for the development of adoptive cell immunotherapies.

Natural microtubules function through biochemical signal-tuned responsiveness. Building intelligent supramolecular assemblies that can emulate dynamic functions is a major challenge facing the field. We designed and synthesized a spiropyran-based inducing ligand that could assemble soybean agglutinin (SBA) into protein nanotubes. During the assembly, tuning of growth dynamics via the light signal resulted in a statistical difference in the average length. Moreover, the nanomechanical properties of the assembled tubes could be tuned via light signals in situ without interfering with the structural integrity, according to the results of liquid-phase Atomic Force Microscopy. Moreover, the SBA tetramer could be released from the assembly into the solution, with the morphology transition from tube to sheet, making a controlled release without harming the protein function. Spiropyran-based protein tubes hold promise for intelligent supramolecular assemblies.