Advanced Healthcare Materials

Therapeutic strategy for efficiently targeting cancer cells needs an in‐depth understanding of the cellular and molecular interplay in the tumor microenvironment (TME). TME comprises heterogeneous cells clustered together to translate tumor initiation, migration, and proliferation. The TME mainly comprises proliferating tumor cells, stromal cells, blood vessels, lymphatic vessels, cancer‐associated fibroblasts (CAFs), extracellular matrix (ECM), and cancer stem cells (CSC). The heterogeneity and genetic evolution of metastatic tumors can substantially impact the clinical effectiveness of therapeutic agents. Therefore, the therapeutic strategy shall target TME of all metastatic stages. Since the advent of nanotechnology, smart drug delivery strategies are employed to deliver effective drug formulations directly into tumors, ensuring controlled and sustained therapeutic efficacy. The state‐of‐the‐art nano‐drug delivery systems are shown to have innocuous modes of action in targeting the metastatic players of TME. Therefore, this review provides insight into the mechanism of cancer metastasis involving invasion, intravasation, systemic transport of circulating tumor cells (CTCs), extravasation, metastatic colonization, and angiogenesis. Further, the novel perspectives associated with current nanotherapeutic strategies are highlighted on different stages of metastasis.

This research focuses on developing and characterizing islatravir‐loaded dissolving microarray patches (MAPs) to provide an effective, minimally invasive treatment option for human immunodeficiency virus (HIV‐1) prevention and treatment. The research involves manufacturing these MAPs using a double‐casting approach, and conducting in vitro and in vivo evaluations. Results show that the MAPs have excellent needle fidelity, structural integrity, and mechanical strength. in vitro studies demonstrate that the MAPs can penetrate skin up to 580 µm and dissolve within 2 hours. Permeation studies reveal that the delivery efficiency of islatravir across the skin is around 40%. In rodent models, these dissolving MAPs sustain islatravir delivery for up to 3 months. Scaling up the MAPs and increasing drug loading produced detectable levels in minipig. Projections from animal data suggest that these dissolving MAPs can achieve effective islatravir levels for a month after a single application in humans. These findings indicate dissolving MAPs as a minimally invasive approach to sustained release of islatravir.

Orthopedic, maxillofacial, and complex dentoalveolar bone grafting procedures that require donor‐site bone harvesting can be associated with post‐surgical complications. There has been widespread adoption of exogenously sourced particulate bone graft materials (BGM) for bone regenerative procedures; however, the particulate nature of these materials may lead to compromised healing outcomes, mainly attributed to structural collapse of the BGM, prolonged tissue healing. In this study, a fully synthetic thermoresponsive hydrogel‐based universal carrier matrix (TX) that forms flowable and shapable putties with different BGMs while spatially preserving the particles in a 3D scaffold at the implantation site is introduced. The potential synergistic effect of the carrier is investigated in combination with particulate demineralized bone matrix (DBM) in a standard muscle pouch nude mice model (n = 24) as well as in a rabbit femoral critical‐sized cortico‐cancellous bone defect model (n = 9). Finally, the clinical usability, safety, and efficacy of the carrier for the delivery of deproteinized bovine bone mineral (DBBM) are evaluated in a controlled clinical trial for extraction socket alveolar ridge preservation (ARP) (n = 11 participants). Overall, the TX carrier improved the delivery of different types of BGMs, maintaining these spatially at the implantation site with minimal inflammatory responses, resulting in favorable bone regenerative outcomes.

The rapid and efficient bone regeneration is still in unsatisfactory outcomes, demonstrating alternative strategy and molecular mechanism is necessary. Nanoscale biomaterials have shown some promising results in enhancing bone regeneration, however, the detailed interaction mechanism between nanomaterial and cells/tissue formation is not clear. Herein, a molecular‐based inorganic–organic nanomaterial poly(citrate‐siloxane) (PCS) is reported which can rapidly enhance osteogenic differentiation and bone formation through a special interaction with the cellular surface communication network factor 3 (CCN3), further activating the Wnt10b/β‐catenin signaling pathway. Further studies revealed that the CCN3 is a key bridge protein for transmitting the osteoinductive effects of nano PCS into the intracellular compartment and activating Wnt10b. Specifically, the molecular mechanism studies confirmed that the inorganic silicon hydroxyl and the organic ester group can bound to the Thrombospondin‐1 (TSP‐1) and von Willebrand factor type C repeat module (vWC) structural domains of CCN3 respectively. The special material‐protein interaction induced a conformational change of CCN3 and activated the function of the TSP‐1 structural domain, which is further associated with the binding and activation of Wnt10b signaling. This study reveals the first targets of nanobiomaterials to promote tissue regeneration through cellular interactions and provides new ideas for the development of materiobiology.

Cell‐instructive polymer hydrogels are instrumental in tissue engineering for regenerative therapies. Implementing defined and selective responsiveness to external stimuli is a persisting challenge that critically restricts their functionality. Addressing this challenge, this study introduces a versatile, modular hydrogel system composed of four‐arm poly(ethylene glycol)(starPEG)‐peptide and glycosaminoglycan(GAG)‐maleimide conjugates. The gel system features a small peptide sequence that is selectively cleaved by the coagulation factor FXa. In a cell culture environment, where active FXa is absent, the hydrogel remains stable, providing a conducive matrix for the growth of complex tissue structures or organoids. Upon the introduction of FXa, the hydrogel is designed to disintegrate rapidly, enabling the gentle release of the cultivated tissues without impairing their functionality. The efficacy of this approach is demonstrated through the ex vivo development, detachment, and transplantation of human corneal endothelial lamellae, achieving sizes relevant for clinical application in Descemet Membrane Endothelial Keratoplasty (DMEK). Furthermore, the practicality of the hydrogel system is validated in vitro using a de‐endothelialized porcine cornea as a surrogate recipient. Since the FXa‐cleavable peptide can be integrated into a variety of multifunctional hydrogels, it can pave the way for next‐generation scaffold‐free tissue engineering and organoid regenerative therapies.

Cancer‐associated fibroblasts (CAFs) are crucial stromal cells in the tumor microenvironment, affecting cancer growth, angiogenesis, and matrix remodeling. Developing an effective in vitro tumor model that accurately recapitulates the dynamic interplay between tumor and stromal cells remains a challenge. In this study, a 3D bioprinted fibroblast ‐ mediated heterogeneous breast tumor model was created, with tumor cells and fibroblasts in a bionic matrix. The impact of transforming growth factor‐β （TGF‐β） on the dynamic transformation of normal fibroblasts into CAFs and its subsequent influence on tumor cells is further investigated. These findings reveales a profound correlation between CAFs and several critical biological processes, including epithelial‐mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, gene expression profiles, and tumor progression. Furthermore, tumor models incorporating CAFs exhibits reduced drug sensitivity compared to models containing tumor cells alone or models co‐cultured with normal fibroblasts. These results underscore the potential of the in vitro fibroblast‐mediated heterogeneous tumor model to simulate real‐life physiological conditions, thereby offering a more effective drug screening platform for elucidating tumor pathogenesis and facilitating drug design prior to animal and clinical trials. This model's establishment promotes the understanding of tumor‐stromal interactions and their therapeutic implications.

The hydrogel adhesives with strong tissue adhesion and biological characteristics adhm202404447are urgently needed for injury sealing and tissue repair. However, the negative correlation between tissue adhesion and the mechanical strength poses a challenge for their practical application. Herein, a bio‐inspired cohesive enhancement strategy is developed to prepare the hydrogel adhesive with simultaneously enhanced mechanical strength and tissue adhesion. The double cross‐linked network is achieved through the cooperation between polyacrylic acid grafted with N‐hydroxy succinimide crosslinked by tannic acid and cohesion‐enhanced ion crosslinking of sodium alginate and Ca²⁺. Such a unique structure endows the resultant hydrogel adhesive with excellent tissue adhesion strength and mechanical strength. The hydrogel adhesive is capable of sealing various organs in vitro, and exhibits satisfactory on‐demand removability, antibacterial, and antioxidant properties. As a proof of concept, the hydrogel adhesive not only effectively halts non‐compressible hemorrhages of beating heart and femoral artery injury models in rats, but also accelerates the healing of infected wound by inhibiting bacteria and reducing inflammation. Overall, this advanced hydrogel adhesive is promising as an emergency rescue adhesive that enables robust tissue closure, timely controlling bleeding, and promoting damaged tissue healing.

The Masquelet technique that combines a foreign body reaction (FBR)‐induced vascularized tissue membrane with staged bone grafting for reconstruction of segmental bone defect has gained wide attention in Orthopedic surgery. The success of Masquelet hinges on its ability to promote formation of a “periosteum‐like” FBR‐induced membrane at the bone defect site. Inspired by Masquelet's technique, here a novel approach is devised to create periosteum mimetics from decellularized extracellular matrix (dECM), engineered in vivo through FBR, for reconstruction of segmental bone defects. The approach involved 3D printing of polylactic acid (PLA) template with desired pattern/architecture, followed by subcutaneous implantation of the template to form tissue, and depolymerization and decellularization to generate dECM with interconnected channels. The dECM matrices produces from the same mice (autologous) or from different mice (allogenic) are used as a functional periosteum for repair of structural bone allograft in a murine segmental bone defect model. This study shows that autologous dECM performed better than allogenic dECM, further permitting local delivery of low dose BMP‐2 to enhance allograft incorporation. The success of this current approach can establish a new line of versatile, patient‐specific, and periosteum‐like autologous dECM for bone regeneration, offering personalized therapeutics to patients with impaired healing.

Here a bioengineered platform is introduced to investigate adverse effects of environmental materials on the human cornea. Using primary cells, this system is capable of reproducing the differentiated corneal epithelium and its underlying stroma in the human eye, which can then be treated with externally applied solid, liquid, or gaseous substances in a controlled manner and under physiologically relevant conditions. The proof‐of‐principle of how this system can be used to simulate human ocular exposure to different classes of environmental toxicants for direct visualization and quantitative analysis of their potential to induce acute corneal injury and inflammation is demonstrated. This model can also be further engineered to create an electromechanically actuated array of multiple human corneal tissues that can emulate spontaneous eye blinking. Using this advanced system, it is shown that blinking‐like mechanical motions may play a protective role against adverse effects of environmental toxicants. This work yields an immediately deployable in vitro technology for screening ocular toxicity of existing and emerging environmental materials of various types and may enable the development of more realistic, human‐relevant preclinical toxicology models complementary to traditional animal testing.

Organic photosensitizers (PSs) possessing NIR‐II emission and photodynamic/photothermal effect have received a great sense of attention for their cutting‐edge applications in imaging‐guided multimodal phototherapy. However, it is highly challenging to design efficient PSs with high luminescence and phototherapy performance simultaneously. In this study, a spiro‐functionalization strategy is proposed to alleviate aggregate‐caused quenching of PSs and promote photodynamic therapy, and the strategy is verified via a spiro[fluorine‐9,9ʹ‐xanthene]‐modified NIR‐II PS (named SFX‐IC) with an acceptor–donor–acceptor configuration. SFX‐IC‐based nanoparticles (NPs) display a high molar extinction coefficient of 7.05 × 10⁴ m‒1 cm⁻¹ at 645 nm due to strong intramolecular charge‐transfer characteristics. As expected, the as‐prepared NPs show strong NIR‐II emission with a fluorescence quantum yield of 1.1%, thanks to the spiro‐configuration that suppressing excessively intermolecular π–π stacking. Furthermore, SFX‐IC NPs not only efficiently generate ¹O2 and O∙−2 under 660 nm laser irradiation, but also possess good photothermal effect with photothermal conversion efficiency of 47.14%. Consequently, SFX‐IC NPs can be served as versatile phototheranostic agents for NIR‐II fluorescence/photoacoustic imaging‐guided phototherapy, manifesting that the spiro‐functionalized strategy is a powerful tool to construct efficient NIR‐II emitting PSs.

To attenuate the intestinal toxicity of chemotherapeutic drugs from rectal suppositories and enhance their chemotherapeutic outcome is greatly significant, but maintains a challenge. In this work, a new strategy of local synergistic hydrogenochemotherapy is proposed to attenuate side effects and enhance therapeutic efficacy based on the anti‐cancer selectivity and normal cells‐protecting effect of H2, and construct a novel anti‐cancer formulation of rectal suppository (5‐FU/CSN@FAG) by fatty acid glycerides (FAG) encapsulating 5‐fluorouracil (5‐FU, a first‐line drug for colorectal cancer treatment) and cerium silicide nanoparticles (CSN) with a sustained hydrolytic H2 release behavior which is synchronous with 5‐FU release. The 3‐week treatment with the suppository once a day can not only completely eradicate colon tumors without tumor recurrence after suppository administration withdrawal, but also efficiently protect the intestinal tract from chemotherapeutic damage. Mechanistically, H2 generated by CSN reduces the toxicity of 5‐FU to normal cells in the intestinal tract by scavenging over‐expressed reactive oxygen species and correcting energy metabolism, and also assists 5‐FU to promote the apoptosis of colon tumor cells by inhibiting their respiration through a CO signaling pathway. High biosafety and therapeutic validity endow the developed suppository with a high potential for clinical translation.

Infectious diabetic wounds pose an arduous threat to contemporary healthcare. The combination of refractory biofilms, persistent inflammation, and retarded angiogenesis can procure non‐unions and life‐threatening complications, calling for advanced therapeutics potent to orchestrate anti‐infective effectiveness, benign biocompatibility, pro‐reparative immunomodulation, and angiogenic regeneration. Herein, embracing the emergent “living bacterial therapy” paradigm, a designer probiotic‐in‐hydrogel wound dressing platform is demonstrated. The platform is constructed employing a “macrogel/microgel/biofilm” hierarchical encapsulation strategy, with Lactobacillus casei as the model probiotic. Alginate gels, in both macro and micro forms, along with self‐produced probiotic biofilms, served as encapsulating agents. Specifically, live probiotics are enclosed within alginate microspheres, embedded into an alginate bulk matrix, and cultivated to facilitate biofilm self‐encasing. This multiscale confinement protected the probiotics and averted their inadvertent escape, while enabling sustained secretion, proper reservation, and localized delivery of therapeutically active probiotic metabolites, such as lactic acid. The resulting biosystem, as validated in vitro/ovo/vivo, elicited well‐balanced antibacterial activities and biological compatibility, alongside prominent pro‐healing, vasculogenic and anti‐inflammatory potencies, thus accelerating the regeneration of infected full‐thickness excisional wounds in diabetic mice. Such multiple encapsulation‐engineered “all‐in‐one” probiotic delivery tactic may shed new light on the safe and efficient adoption of live bacteria for treating chronic infectious diseases.

Bacterial infections can lead to severe medical complications, including major medical incidents and even death, posing a significant challenge in clinical trauma repair. Consequently, the development of new, efficient, and non‐resistant antimicrobial agents has become a priority for medical practitioners. In this study, a stepwise hydrothermal reaction strategy is utilized to prepare Fe3O4@MoS2 core–shell nanoparticles (NPs) with photosynthesis‐like activity for the treatment of bacterial infections. The Fe3O4@MoS2 NPs continuously catalyze the production of reactive oxygen species (ROS) from hydrogen peroxide through photosynthesis‐like reactions and convert light energy into heat with a photothermal efficiency of 30.30%. In addition, the photosynthetically generated ROS, combined with the iron‐induced cell death mechanism of the Fe3O4@MoS2 NPs, confer them with exceptional and broad‐spectrum antibacterial properties, achieving antimicrobial activities of up to 98.62% for Staphylococcus aureus, 99.22% for Escherichia coli, and 98.55% for methicillin‐resistant Staphylococcus aureus. The composite exhibits good cell safety and hemocompatibility. Finally, a full‐thickness diabetic wound model validates the significant pro‐healing properties of Fe3O4@MoS2 in chronic diabetic wounds. Overall, the design of photosynthesis‐inspired Fe3O4@MoS2 presents new perspectives for developing efficient photothermal nano‐enzymatic compounds, offering a promising solution to the challenges of antimicrobial drug resistance and antibiotic misuse.

Introducing multiple physical cues to control cell behaviors effectively is considered as a promising strategy in developing bioactive wound dressings. Silk nanofiber‐based cryogels are developed to favor angiogenesis and tissue regeneration through tuning hydrated state, microporous structure, and mechanical property, but remained a challenge to endow with more physical cues. Here, β‐sheet rich silk nanofibers are used to develop cryogels with nanopore structure. Through optimizing crosslinking time and exposing the reactive group inside the nanofibers, the crosslinking reaction is improved to induce stable cryogel formation. Besides the hydrated state and macroporous structure, the nanopore structure formed on the macroporous walls, providing hierarchical microstructures to improve cell migration. Both in vitro and in vivo results reveal quicker cell migration inside the cryogels, which then accelerates angiogenesis and wound healing. The mechanical properties can further regulate to match with skin regeneration. The wound healing study in vivo reveals lower inflammatory factor secretion in the wounds treated with softer cryogels with nanopores, which then resulted in the best angiogenesis and wound healing with less scar. Therefore, the porous cryogels with multiple physical cues can be fabricated with silk nanofibers to control cell behaviors and tissue regeneration, providing a promising approach for designing bioactive wound dressings.

Glucocorticoids (GCs) are standard‐of‐care treatments for inflammatory and immune disorders, and their long‐term use increases the risk of osteoporosis. Although GCs decrease bone functionality, their role in bone microvasculature is incompletely understood. Herein, the study investigates the mechanisms of bone microvascular barrier function via osteoblast‐endothelial interactions in response to GCs. The animal data shows that prednisolone (Psl) downregulated the osteoblast function and microvessel number and size. To investigate the role of GCs in bone endothelial barrier function further, a bicellular microfluidic in vitro system is developed and utilized, which consists of three‐dimensional (3D) perfusable microvascular structures embedded in collagen I/osteoblast matrix. Interestingly, it is demonstrated that GCs significantly inhibit osteogenesis and microvascular barrier function by interfering with endothelial‐osteoblast interactions. This effect is triggered by MAPK‐induced phosphorylation of connexin43 (Cx43) at Ser282. Collectively, this study sheds light on microvascular function in bone disorders, as osteoporosis, and permits to capture dynamic changes in endothelial‐bone interactions under GCs by dissecting the MAPK/Cx43 mechanism and proposing this as a potential target for bone diseases.

Redox imbalance, including excessive production of reactive oxygen species (ROS) caused by mitochondrial dysfunction and insufficient endogenous antioxidant capacity, is the primary cause of myocardial ischemia‒reperfusion (I/R) injury. In the exploration of reducing myocardial I/R injury, it is found that protecting myocardial mitochondrial function after reperfusion not only reduces ROS bursts but also inhibits cell apoptosis triggered by the release of cytochrome c. Additionally, nuclear factor erythroid 2‐related factor 2 (Nrf2) is considered a potential therapeutic target for treating myocardial I/R injury by enhancing the cellular antioxidant capacity through the induction of endogenous antioxidant enzymes. In this study, a peptide‒drug conjugate OI‐FFG‐ss‐SS31(ISP) is developed by integrating the Nrf2 activator 4‐octyl itaconate (OI) and the mitochondria‐targeting protective peptide elamipretide (SS31), and its therapeutic potential for myocardial I/R injury is explored. The results showed that ISP could self‐assemble into nanofibers in response to the acidic microenvironment and bind to Keap‐1 with high affinity, thereby activating Nrf2 and enhancing antioxidant capacity. Simultaneously, the release of SS31 could improve mitochondrial function and reduce ROS, ultimately providing a restoration of redox homeostasis to effectively alleviate myocardial I/R injury. This study presents a promising acid‐triggered peptide‐drug conjugate for treating myocardial I/R injury.

Mimicking compositions and structures of extracellular matrix is widely studied to create in vitro tumor models, to deepen the understanding of the pathogenesis of the different types of cancer, and to identify new therapies. On the other hand, the use of synthetic materials to modulate cancer cell biology and, possibly, to reduce the malignancy of cancer cells through their exploitation is far less explored. Here, the study evaluates the effects of Liquid Crystalline Networks (LCNs) based scaffolds on the growth of A375 metastatic melanoma cells. Interestingly, cells grown on such materials show reduced cell proliferation and colony‐forming capacity with respect to those cultivated on standard plates. These effects are associated with a higher percentage of senescent cells and a shift to a more epithelial phenotype, pointing to the occurrence of a mesenchymal to epithelial transition. All these biological outcomes are affected by the amount of crosslinker in the material and have been induced only thanks to the interactions with the polymeric substrate without the need of further chemical (e.g., specific growth factor) or physical (e.g., irradiation) stimuli, opening to the possible development of anti‐cancer coatings.

The rational design of self‐assembled compounds is crucial for the highly efficient development of carrier‐free nanomedicines. Herein, based on computer‐aided strategies, important physicochemical properties are identified to guide the rational design of self‐assembled compounds. Then, the pharmacophore hybridization strategy is used to design self‐assemble nanoparticles by preparing new chemical structures by combining pharmacophore groups of different bioactive compounds. Hydroxychloroquine is grafted with the lipophilic vitamin E succinate and then co‐assembled with bortezomib to fabricate the nanoparticle. The nanoparticle can reduce M2‐type tumor‐associated macrophages (TAMs) through lysosomal alkalization and induce immunogenic cell death (ICD) and nuclear factor‐κB (NF‐κB) inhibition in tumor cells. In mouse models, the nanoparticles induce decreased levels of M2‐type TAMs, regulatory T cells, and transforming growth factor‐β (TGF‐β), and increase the proportion of cytotoxicity T lymphocytes. Additionally, the nanoparticles reduce the secretion of Interleukin‐6 (IL‐6) by inhibiting NF‐κB and enhance the programmed death ligand‐1 (PD‐L1) checkpoint blockade therapy. The pharmacophore hybridization‐derived nanoparticle provides a dual‐modulation strategy to reprogram the tumor microenvironment, which will efficiently enhance the chemoimmunotherapy against triple‐negative breast cancer.

The complex composition of traditional Chinese medicines (TCMs) has posed challenges for in‐depth study and global application, despite their abundance of bioactive compounds that make them valuable resources for disease treatment. To overcome these obstacles, it is essential to modernize TCMs by focusing on precise disease treatment. This involves elucidating the structure‐activity relationships within their complex compositions, ensuring accurate in vivo delivery, and monitoring the delivery process. This review discusses the research progress of TCMs in precision disease treatment from three perspectives: spatial multi‐omics technology for precision therapeutic activity, carrier systems for precise in vivo delivery, and medical imaging technology for visualizing the delivery process. The aim is to establish a novel research paradigm that advances the precision therapy of TCMs.

Dry eye disease (DED) is a multifaceted ocular surface disorder that significantly impacts patients’ daily lives and imposes a substantial economic burden on society. Oxidative stress, induced by the overproduction of reactive oxygen species (ROS), is a critical factor perpetuating the inflammatory cycle in DED. Effectively scavenging ROS is essential to impede the progression of DED. In this study, boronophenylalanine‐ containing polydopamine (PDA‐PBA) nanoparticles are developed loaded with melatonin (MT), which are blended with poly(vinyl alcohol) (PVA) to create eye drops PVA/ PDA‐PBA@MT (PPP@MT). In vitro and in vivo studies demonstrate that PPP@MT exhibits dual functionalities in reducing ROS production and downregulating inflammatory pathways, thereby preserving mitochondrial integrity and further inhibiting programmed cell death. Following PPP@MT treatment, tear secretion, corneal structure, and the number of goblet cells are markedly restored in a mouse model of dry eye, indicating the therapeutic efficacy of this agent. Collectively, PPP@MT, characterized by minimal side effects and favorable bioavailability, offers promising therapeutic insights for the management of DED and other ROS‐mediated disorders.

Photosensitizers (PSs) featuring type I reactive oxygen species (ROS) generation and aggregation‐induced emission (AIE) activity offer a promising solution to achieve non‐invasive and precise theranostics. However, the reported AIE luminogens (AIEgens) with both AIE characteristic and strong type‐I ROS generation are still scarce and the structure‐property relationship is still unclear. Herein, an innovative acceptor elongation boosted intersystem crossing (AEBIC) design strategy has been proposed to endow the AIEgen strong type‐I ROS producibility. The results indicate that the obtained AIEgen exhibit type‐I ROS and aggregation‐enhanced ROS efficacy, which has been verified by both experimental and theoretical results. Mechanistic study reveal that the acceptor elongation has promoted a dual‐channel intersystem crossing pathway to enhance the intersystem crossing (ISC) process due to the differences in triplet configurations, which can be further amplified by aggregation. The afforded type‐I AIE‐PS show lipid droplet‐anchored characteristic and can induce the ferroptosis through destroying the cellular redox homeostasis and increasing lethal levels of lipid peroxidation. Finally, targeting ferroptosis‐based cancer therapy can be realized with excellent anti‐tumor effect.

Liver ischemia and reperfusion (I/R) injury is a reactive oxygen species (ROS)‐related disease that occurs during liver transplantation and resection and hinders postoperative liver function recovery. Current approaches to alleviate liver I/R injury have limited effectiveness due to the short circulation time, poor solubility, and severe side effects of conventional antioxidants and anti‐inflammatory drugs. Herein, a universal strategy is proposed to fabricate a Trojan horse‐like biohybrid nanozyme (THBN) with hepatic‐targeting capabilities. Tannic acid (TA) mediates adeno‐associated virus (AAV8) decoration onto 2D Ti3C2 nanosheets, resulting in THBN with a size of 116.2 ± 9.5 nm. Remarkably, THBN exhibits catalase (CAT)‐like activity, broad‐spectrum ROS scavenging activity and targeted delivery to liver tissue owing to the presence of AAV8. Both in vivo and in vitro experiments confirmed the efficacy of THBN in attenuating liver I/R injury by mitigating inflammation and oxidative stress and inhibiting hepatocellular apoptosis. RNA‐seq analysis suggests that THBN may alleviate liver I/R injury by activating the PKC pathway. The effective targeting and therapeutic capabilities of THBN represent an advancement in nanotherapeutics for hepatic ischemia‒reperfusion injury, shedding light on the promising potential of this next‐generation nanotherapeutic approach.

Anterior cervical spine surgeries are often complicated by difficulty swallowing due to local postoperative swelling, pain, scarring, and tissue dysfunction. These postoperative events lead to systemic steroid and narcotic use. Local, sustained drug delivery may address these problems, but current materials are unsafe for tight surgical spaces due to high biomaterial swelling, especially upon degradation. To address these shortcomings, a low‐swelling, amphiphilic hydrogel system termed DexaPatch is developed containing dexamethasone‐poly(lactic‐co‐glycolic acid) (PLGA) microparticles for sustained release upon local implantation in the surgical site. The bulk amphiphilic hydrogel, comprised of 4‐arm poly(ethylene glycol) (PEG)‐maleimide macromer cross‐linked with triblock dithiolated PEG‐poly(propylene glycol)‐PEG (poloxamer a.k.a. Pluronic), achieves consistent and tunable mechanical and low‐swelling properties. Dexamethasone is released in a burst, followed by a sustained release over 40 days, similar to the release from microparticles alone. The DexaPatch system is lyophilized for shelf stability and surgical handling properties, sterilized, and briefly rehydrated in the operating room prior to surgical implantation in a rabbit model of anterior spinal surgery. DexaPatch results in significantly reduced prevertebral edema radiographically and decreased fibrosis in prevertebral muscles compared to sham surgery. This implantable biomaterial platform reduces local postoperative inflammation with potential surgical applications throughout the body.

Nowadays, gastroesophageal reflux disease (GERD) has emerged as one of the major hazards to the health of the upper gastrointestinal tract, and there is an urgent need for a low‐cost, user‐friendly, and non‐invasive detection method. Herein, a paper‐based sensor (CP sensor) for the non‐invasive screening of GERD is proposed. The sensor is structured as a specially shaped cellulose paper strip embedded with fluorescent colloids, which are self‐assembled from a cleavable synthetic fluorescent polymer (P4). Benefiting from the introduction of amide bonds and the unique assembled structure of the nanocolloids, the pepsin in the sample solution will hydrolyze the water‐soluble branches in the micellar shell during detection, resulting in a corresponding output of the fluorescent signal. This responsiveness, which can be observed by the naked eye, is so sensitive with a minimum detectable concentration for pepsin as low as 0.3 ng·mL⁻¹. Clinical trials have further demonstrates that the designed paper sensor is capable of providing improved accuracy in the early diagnosis of GERD.

Aging is one of the most significant risk factors for breast cancer. With the growing interest in the alterations of the aging breast tissue microenvironment, it is identified that aging is related to tumorigenesis, invasion, and drug resistance. However, current pre‐clinical disease models often neglect the impact of aging and sometimes result in worse clinical outcomes. In this study, aged animal‐generated materials are utilized to create and validate a novel age‐mimetic breast cancer model that generates an aging microenvironment for cells and alters cells toward a more invasive phenotype found in the aged environment. Furthermore, the age‐mimetic models are utilized for 3D breast cancer invasion assessment and high‐throughput screening of over 700 drugs in the FDA‐approved drug library. 36 potential effective drug targets as well as 34 potential drug targets with different drug responses in different age groups are identified, demonstrating the potential of this age‐mimetic breast cancer model for further in‐depth breast cancer studies and drug development.