Biomaterials serve as bridges between synthetic structures and biological systems, facilitating interactions with bodily tissues and regulating cellular responses. However, the intricate mechanisms governing cell-material interactions within the body are not fully understood. To address these challenges, single-cell transcriptomics and spatial technologies have emerged as promising tools. This review introduces the concept of the 'Biomaterial-mediated Cell Atlas' and summarizes its recent advances in biomaterials research. Building upon the framework of the Human Cell Atlas, it can extend its scope to include biomaterial-mediated cellular responses. The principles and workflows of single-cell and spatial transcriptomics are then presented, emphasizing their potential to reveal cellular diversity and spatial arrangements affecting material-cell interactions. Furthermore, transcriptomics-driven approaches are highlighted for their potential in mapping biomaterial-cell communication pathways, which are essential for elucidating biological mechanisms and guiding material design. Challenges inherent to current methodologies and emerging frontiers in this interdisciplinary field are discussed.

Achieving rapid hemostasis, infection control, and tissue regeneration remains a central challenge in acute wound management, particularly under emergency and battlefield conditions. Current hemostatic materials often suffer from delayed coagulation, low bioactivity, and potential immunogenicity, limiting their use in critical care. Here, we present a chemically engineered charged silk-based hydrogel (SAMA) that integrates ultrafast gelation, intrinsic antibacterial activity, and programmable biological function. SAMA is synthesized via dual side-chain modification of silk fibroin with methacrylate (MA) for photo-crosslinking and dimethylamino groups (DMA) for surface charge tuning. The hydrogels enable photo-triggered crosslinking within 8 s under 405 nm light, while offering programmable surface charge and aqueous stability. The positively charged SAMA-5.0(+) hydrogel markedly enhances coagulation and platelet activation, as evidenced by reduced blood loss, shortened clotting time, and elevated CD62P+/PAC-1+ platelet populations. The hydrogels exhibit over 95 % antibacterial efficacy against Staphylococcus aureus and Escherichia coli, while maintaining excellent cytocompatibility, hemocompatibility, and promoting favorable responses in endothelial and immune cells. Mechanistically, SAMA(+) induces macrophage polarization toward the anti-inflammatory M2 phenotype, suppressing IL-6-mediated inflammation and facilitating angiogenesis and collagen remodeling. Controlled release assays demonstrate first-order kinetics for both the model protein (BSA) and ropivacaine, enabling sustained and timely delivery under neutral and mildly acidic wound environments. These findings position charged SAMA hydrogels as a clinically translatable solution for acute wound care, integrating rapid sealing, antimicrobial protection, immune regulation, and tissue repair into a low-cost platform suitable for wound and emergency applications.

The multidimensional complexity between metabolism and inflammation within the obese tumor microenvironment (OTME) poses substantial barriers to postsurgical immunotherapy and wound management. Herein, we engineered a multifunctional hydrogel (Lipo/CXB@Hydrogel) through covalent conjugation of dopamine-crosslinked oxidized hyaluronic acid and a ROS-sensitive linker, co-delivering the non-steroidal anti-inflammatory drug celecoxib (CXB) and the lipid metabolism modulator Lipofermata (Lipo) to facilitate T cell immunotherapy and wound healing. The unique multi-dynamic-bond crosslinked structure endows the hydrogel with excellent self-healing, tissue adhesiveness and mechanical properties. The implanted Lipo/CXB@Hydrogel degrades and releases CXB to suppress hyperinflammation and enhance intratumoral cytotoxic T lymphocyte (CTL) infiltration, while Lipo inhibits the predatory uptake of fatty acids by tumor cells in the OTME for competing metabolic resources of intratumoral infiltrated CTLs. Importantly, such a cascaded immunological effect of Lipo/CXB@Hydrogel treatment amplifies CTL proliferation and activity specifically through targeting the arachidonic acid (AA)/COX-2/PGE2 signaling axis, a central hub linking lipid metabolism and inflammation, initiating a long-lasting immune response to suppress colorectal tumor postsurgical recurrence and metastasis in obesity contexts. Moreover, the hydrogel can easily repeatedly close the reopened wounds and promote skin regeneration. Thus, this multifunctional hydrogel may provide a promising strategy for postsurgical obese tumor immunotherapy and wound closure.

The complex bone repair microenvironment remains a significant challenge in orthopedics. As pivotal regulators, bioactive metal ions can promote osseointegration by coordinating the bone immune microenvironment. To address this, we engineered Zn2+/Ce3+ double-doped whitlockite nanoparticles (Zn2+/Ce3+-WH) via a biomimetic GelMA template (GM&Zn2+/Ce3+-WH). These biomimetic GM&Zn2+/Ce3+-WH hydrogel scaffolds exhibit excellent antioxidant, significantly activated anti-inflammatory macrophage phenotypes and inhibited osteoclastogenesis. The resulting immune microenvironment favorably promoted osteogenic differentiation in vitro and facilitated implant-to-bone osteointegration in vivo. Additionally, the scaffolds demonstrated potential for post-operative anti-infection activity. Notably, GM&Zn2+/Ce3+-WH exhibited excellent overall performance. In summary, the natural bone-like Zn2+/Ce3+ co-doping strategy endows GM&Zn2+/Ce3+-WH with immunomodulatory, bacteriostatic, and osseointegrative properties, offering a distinctive and promising approach to re-establishing an immunoregulated osteogenic microenvironment for bone regeneration.

The bone unit (BU) is a multicellular functional unit composed of neuromodulatory networks, bone tissue, and functional blood vessels. As a functional extension of bone regeneration, the BU coordinates neural signal, regeneration of the circulatory network and remodeling of the bone matrix through the neural-bone metabolic coupling mechanism. Currently, effective strategies are lacking to remodel the homeostasis of the neural-bone metabolic coupling, which in turn leads to impaired BU regeneration. Here, we constructed a 3D-printed biomimetic hydrogel scaffold, GGMN-GSE, to synergistically couple nerve-bone metabolism and restore BU regeneration through electrophysiological microenvironment reconstruction and functional cell recruitment. The GGMN layer (Grooved GelMA@MXene@NGF) incorporates conductive MXene to emulate periosteal electrophysiology and features biomimetic microgrooves to guide neural orientation, collectively modulating neural-bone metabolic coupling. The GSE layer (GelMA@SVVYGLR-E7), engineered with a dual-targeting peptide, recruits BMSCs/EPCs to supply functional cells while remodeling the vasculo-osseous regenerative niche, synergistically driving osteogenic regeneration. In vitro, the GGMN-GSE scaffold promoted nerve fiber regeneration and induced secretion of neuropeptides such as CGRP, GHRH, and VIP, and activated Calcrl, Ghr, Vipr, and other receptors on the surface of BMSCs, driving BU regeneration. This effect was mediated by neural-bone metabolic coupling through the PI3K-Akt/STAT5 signaling axis. In vivo, compared with the control group, the density of CGRP+ nerves in the GGMN-GSE group increased by 2.9-fold, the density of CD31+ blood vessels in the GGMN-GSE group increased by 1.8-fold, the area of the neogenetic bone matrix expanded by 3.6-fold, and the BV/TV reached 97.1 % in the CT. Confocal analysis of rat calvarial defects established that GGMN-GSE scaffolds exclusively promoted synergistic 3D co-localization of neural networks, functionalized vasculature, and osseous tissue, which drove multi-scale BU regeneration. The 3D-printed scaffolds fabricated in this study effectively remodel neural-bone metabolic coupling homeostasis to treat critical bone defects.

Supramolecular hydrogels derived from low-molecular-weight gelators (LMWGs) have attracted considerable interest in drug delivery due to their exceptional biocompatibility and responsiveness to physiological microenvironments. However, fabricating microgel formulations based on LMWGs is extremely challenging due to the intrinsic fragility of the self-assembled networks. To mitigate the thermodynamic limitation of LMWGs, we developed an in-droplet self-assembly strategy to fabricate spherical supramolecular microgels. In this approach, mild droplet solidification ensures that ascorbyl palmitate (AP) molecules self-assemble into nanosheets through hydrophobic interactions and hydrogen bonding. As the droplets shrink, these nanosheets concentrate, interpenetrate with each other and form stable microgels. The palmitate-based prodrugs were successfully incorporated into the interdigitated bilayer structure, achieving high drug-loading degree (36.4–47.2 wt%). In vitro and in vivo studies confirmed the inflammation-responsive disassembly of these microgels, leading to flare-dependent, on-demand drug release. While both formulations exhibited comparable therapeutic efficacy in a standard inflammatory arthritis (IA) model, the disease-severity adaptive microgels demonstrated markedly superior therapeutic benefits in a severe IA model compared to non-responsive microspheres designed to resemble clinically utilized formulations. Overall, our results suggest inflammation-responsive supramolecular microgels enabled by controlled in-droplet self-assembly represent a promising next-generation platform for localized drug delivery, with strong potential for clinical translation.

Bone tissue destruction and related complications caused by bacterial infection remain a major challenge in clinical treatment. Existing therapies generally fail to balance the process of infection control and tissue repair simultaneously. In this study, infection microenvironmental-responsive multifunctional "molecular sprayer" nanocomposites (NP@D/AMP) were developed by loading 2-(1, 8-naphthidine -2-yl) phenol (2-NP) onto dendritic mesoporous silica nanoparticles (DMSNs), then encapsulating GW18 with polydopamine for sealing, which achieved the integrated functions of antibacteria, immune regulation and promoting bone formation. NP@D/AMP can sequentially release GW18 and 2-NP under the acidic microenvironment at the infectious site, where GW18 shows strong antibacterial and biofilm inhibition ability against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) through electrostatic interaction as well as 2-NP activates macrophages into M1 macrophages to synergistically enhance the antibacterial immune response and improve the inflammatory microenvironment. Notably, NP@D/AMP can also significantly promote osteogenic differentiation in vitro and accelerate bone repair in vivo. In brief, nanocomposite NP@D/AMP has demonstrated sustained and surprising antibacterial activity with macrophage regulation and bone formation efficacy in the treatment model of bone infection. Our study provides an innovative "antibacteria - immune balance - tissue repair" synergistic integrated therapy strategy for infectious bone defects.

Dental implants are the primary solution for tooth replacement, providing both aesthetic and functional restoration. Their long-term success depends not only on osseointegration but also on robust peri-implant soft tissue integration (PSTI), particularly in the transmucosal region, where a stable epithelial seal is critical to preventing microbial infiltration and peri-implant inflammation. While surface topography modifications such as roughness, morphology, and porosity influence gingival cell behavior, passive surface modifications alone are often insufficient to promote rapid PSTI. This raises a fundamental question in dental implant design: How can implant surfaces be bioengineered to actively promote PSTI rather than passively relying on cellular responses? This review examines how biofunctionalization has emerged as a transformative strategy in implant surface engineering and critically analyses the latest biofunctionalization strategies for dental implants, with a particular focus on the underlying mechanisms that regulate biomolecule-implant interactions. It evaluates biomolecule incorporation via physical and covalent attachment, highlighting their distinct advantages in stability, efficiency, and scalability. We discuss approaches for functionalizing dental implant surfaces with bioactive molecules, such as proteins and peptides, and cells to replicate natural biological interactions, regulate immune responses, and enhance antimicrobial defense mechanisms. By addressing how bioengineered surfaces can be designed to actively engage with biological systems, this review provides a framework for developing next-generation implant technologies that achieve more effective and predictable PSTI, with strong potential for clinical translation.