Pengchao Zhao

Healthy articular cartilage maintains ultralow friction through the lipid/hyaluronic acid/lubricin complex lubrication layer, in which the zwitterionic lipids mediate lubrication and the hyaluronic acid and lubricin anchor to cartilage matrix. However, in osteoarthritis this lubrication system is progressively degraded, leading to increased cartilage wear and joint dysfunction. Therefore, early and lubrication-based intervention is urgently needed. Here we present biomimetic polyzwitterionic coacervates (pZCOs) that recapitulate both the lubrication and cartilage-binding functionalities of the natural boundary lubrication layer. pZCOs exhibit strong binding affinity to fibronectin, establish a stable and ultralow-friction lubrication layer on the cartilage surface, facilitate the sustained release of anti-inflammatory drugs, and preserve the viability and anti-inflammatory paracrine secretion of encapsulated mesenchymal stem cells. In both rat and mini-pig models of osteoarthritis, intra-articular administration of drug/MSC-laden pZCOs effectively reduces cartilage degradation, suppresses inflammation and promotes cartilage integrity, outperforming clinical hyaluronic acid lubricants in lubrication performance, in vivo retention and therapeutic efficacy. These findings highlight the translational potential of engineered biomimetic coacervates as next-generation joint lubricants for integrated management of osteoarthritis.

Current therapies for inflammatory skin diseases predominantly rely on broad systemic immunosuppression and lack precision toward defined immune‐cell subsets. Here, we identify CX3CR1 ⁺ nonclassical monocytes (NCMs) as an inflammatory monocyte subset that contributes to the amplification of psoriasiform inflammation, as supported by integrated analyses of human single‐cell transcriptomics, genetic depletion, and adoptive‐transfer models. To preferentially engage these disease‐associated NCMs, we engineer an artificial cell–microneedle platform, termed CX3@GUV‐DMF, comprising CX3CL1‐functionalized, drug‐loaded giant unilamellar vesicles (GUVs) embedded within a dissolvable hyaluronic acid (HA) microneedle array. Following intradermal insertion, surface‐presented CX3CL1 actively navigates GUVs to pathogenic CX3CR1 ⁺ NCMs, facilitating the targeted, sustained release of the loaded drug. In vivo evaluations and transcriptomic profiling demonstrate that this localized immunomodulatory strategy attenuates inflammatory myeloid activation, neutrophil infiltration, and Th17‐associated responses while promoting restoration of epidermal barrier‐associated programs. These findings establish a materials‐enabled strategy for subset‐oriented immune modulation and local inflammatory‐niche remodeling, advancing inflammatory skin therapy beyond nonspecific immunosuppression.

Developing adhesives with robust underwater adhesion to diverse substrates, particularly highly hydrated and lipidic substrates, remains a major challenge. Inspired by the tough adhesion of barnacles on marine creatures, here we report a dilution-resistant and superspreading coacervate to mediate robust underwater adhesion by enabling interfacial infiltration and intertwining. Conjugation of terminal butyl groups to poly(propylene glycol) (PPG) triggers liquid-liquid phase separation of the aqueous solution and formation of PPG coacervate driven by the hydrogen bonding and hydrophobic interactions. The simple coacervate shows distinctive superspreading properties to facilitate interfacial wetting, infiltration and formation of intertwined interfaces on both the hydrated and lipidic substrates and concentrates the loaded hydrophilic curing agents to form a robust underwater adhesive by rapid in situ photocuring. The coacervate-based adhesive demonstrates strong underwater adhesion to diverse substrates, including highly hydrated and lipidic substrates with multiscale porosity and in complex aqueous environments. Potential applications of this adhesive are validated by robust adhesion-mediated hydrogel and/or organogel assemblies and effective sealing of underwater leakages and tissue perforations.

Diabetic wounds present a pressing clinical challenge due to their self‐perpetuating pathological microenvironment, where oxidative stress, the accumulation of advanced glycation end‐products and their receptors (AGE‐RAGE), and chronic inflammation form a vicious cycle that impedes healing. The effective delivery of therapeutic agents by existing antioxidant hydrogels is compromised by their poor conformability to complex wound geometries due to rapid crosslinking kinetics, resulting in the failure to correct these interconnected pathological processes. Here, we synthesize an organoselenium polymer (OSP) capable of microphase‐separation to extend acylhydrazone crosslinking kinetics, thereby producing a tissue‐conforming organoselenium hydrogel (TCOH) that effectively presents organoselenium motifs to the pathological diabetic wound bed. The TCOH can effectively restore redox homeostasis, enhance angiogenesis, and reprogram the immune microenvironment by promoting M2 macrophage polarization. Transcriptomic profiling and Western Blot analyses concurrently confirm the restoration of glycolipid metabolism and suppression of AGE‐RAGE and NF‐κB signaling. This multifaceted restoration of the pro‐healing microenvironment results in accelerated wound closure, enhanced collagen deposition, and functional tissue regeneration. Our work establishes a new paradigm in chronic wound management by integrating dynamic material adaptation with multi‐targeted pathological regulation, offering a promising therapeutic platform for various redox‐ and AGE‐related chronic diseases.

The effective treatments of biofilm‐related refractory infections such as osteomyelitis are hampered by the limited drug coverage to large infected areas and infiltration into the biofilm at infection sites. Herein, guided by the hypothesis that liquid water‐immiscible coacervates with ultra‐low interfacial tension could effectively infiltrate these barriers, it is systematically screened 7 representative coacervates for their biofilm infiltration performance. Coacervates with ultra‐low interfacial tension (− ¹ ) showed markedly enhanced biofilm infiltration, whereas a high‐interfacial‐tension control (Gel‐Nap coacervate) and aqueous controls failed to infiltrate biofilms. However, electrostatically assembled complex coacervates suffered from poor physiological stability and cytotoxicity. The physiologically stable and biocompatible PEG‐alkyl coacervate is selected as a lead candidate for in vivo validation. In murine and canine osteomyelitis models, the selected drug‐loaded PEG‐alkyl coacervate system further demonstrated robust infiltration of microporous bone and dense biofilm, sustained local drug retention, effective eradication of Staphylococcus aureus , suppression of inflammatory cytokines, and accelerated bone regeneration. This study establishes low‐interfacial‐tension–driven infiltration as a generalizable principle for designing stable and biocompatible fluidic coacervate carriers to eradicate refractory biofilm infections.

The propensity for controlled liquid–liquid phase separation and subsequent directed phase transition are crucial for the coacervation-mediated assembly of extracellular matrix (ECM). This spatiotemporally controlled ECM assembly can be used to develop coacervate-based polymer assembly strategies to generate biomimetic materials that can emulate the complex structures and biophysical cues of the ECM. Inspired by the tropoelastin structure, here we develop a designer minimalistic model consisting of alternating hydrophobic moieties and covalent crosslinking domains. By increasing the valence and enhancing the interaction strength of the hydrophobic moieties, we can control the degree of the assembly to enhance the propensity for phase separation and thus emulate the extracellular coacervation process of tropoelastin, including droplet formation, coalescence and maturation. The subsequent covalent-bonding-triggered coacervate–hydrogel transition with enhanced assembly order stabilizes the phase-separated structure in the form of a heterogeneous hydrogel, thereby mimicking covalent crosslinking-derived elastin fibrillation. Furthermore, the heterogeneous hydrogel network establishes a biomimetic matrix that can effectively promote the mechanosensing of adherent stem cells.

Mesenchymal condensation, characterized by rapid proliferation and aggregation of precursor cells within a restructured mesodermal extracellular matrix, is critical for skeletal tissue development, including articular cartilage. This process establishes a hypoxic microenvironment that drives metabolic shifts and epigenetic modifications essential for cartilage development. To replicate this, we engineer a cell-adaptable supramolecular hydrogel that accommodates the extensive volumetric and morphological changes of encapsulated mesenchymal stromal cells, facilitating the rapid formation of large multicellular cartilaginous organoids. This adaptation fosters a hypoxic environment and induces metabolic shifts toward glycolysis, increasing lactate accumulation and histone lysine lactylation. Enhanced lactylation on Lysine 18 of Histone H3 promotes chondrogenesis and cartilage matrix deposition by improving the accessibility of chondrogenic genes, while the inhibition of histone lactylation disrupts these processes. Implantation of the ultradynamic hydrogel in large animal cartilage defects results in superior repair compared to less dynamic alternatives, providing insights for effective biomaterial delivery in cell therapies. Our findings reveal how matrix biophysical cues influence cellular development, metabolic reprogramming, and epigenetic modifications.

The native extracellular matrix is continuously remodeled to form complex interconnected network structures that reversibly regulate stem cell behaviors. Both regulation and understanding of its intricate dynamicity can help to modulate numerous cell behaviors. However, neither of these has yet been achieved due to the lack of designing and modeling such complex structures with dynamic controllability. Here we report modularity-based mathematical modeling of extracellular matrix-emulating ligand inter-cluster connectivity using the graph theory. Increasing anisotropy of magnetic nano-blockers proportionately disconnects arginine-glycine-aspartic acid ligand-to-ligand interconnections and decreases the number of ligand inter-cluster edges. This phenomenon deactivates stem cells, which can be partly activated by linearizing the nano-blockers. Remote cyclic elevation of high-anisotropy nano-blockers flexibly generates nano-gaps under the nano-blockers and augments the number of ligand inter-cluster edges. Subsequently, integrin-presenting stem cell infiltration is stimulated, which reversibly intensifies focal adhesion and mechanotransduction-driven differentiation both in vitro and in vivo. Designing and systemically modeling extracellular matrix-mimetic geometries opens avenues for unraveling dynamic cell-material interactions for tissue regeneration.