Degradable and Recyclable Hydrogels for Sustainable Bioelectronics.

Hydrogel bioelectronics has been widely used in wearable sensors, electronic skin, human-machine interfaces, and implantable tissue-electrode interfaces, providing great convenience for human health, safety, and education. The generation of electronic waste from bioelectronic devices jeopardizes human health and the natural environment. The development of degradable and recyclable hydrogels is recognized as a paradigm for realizing the next generation of environmentally friendly and sustainable bioelectronics. This review first summarizes the wide range of applications for bioelectronics, including wearable and implantable devices. Then, the employment of natural and synthetic polymers in hydrogel bioelectronics is discussed in terms of degradability and recyclability. Finally, this work provides constructive thoughts and perspectives on the current challenges toward hydrogel bioelectronics, providing valuable insights and guidance for the future evolution of sustainable hydrogel bioelectronics.

Micropatterned shape-memory polymer substrate containing hydrogen bonds creates a long-term dynamic microenvironment for regulating nerve-cell fate.

Peripheral nerve injuries (PNIs) caused by mechanical contusion are frequently encountered in clinical practice, using nerve guidance conduits (NGCs) is now a promising therapy. An NGC creates a microenvironment for cell growth and differentiation, thus understanding physical and biochemical cues that can affect nerve-cell fate is a prerequisite for rationally designing NGCs. However, most of the previous works were focused on some static cues, the dynamic nature of the nerve microenvironment has not yet been well captured. Herein, we develop a micropatterned shape-memory polymer as a programmable substrate for providing a dynamic cue for nerve-cell growth. The shape-memory properties enable temporal programming of the substrate, and a dynamic microenvironment is created during standard cell culturing at 37 °C. Unlike most of the biomedical shape-memory polymers that recover rapidly at 37 °C, the proposed substrate shows a slow recovery process lasting 3-4 days and creates a long-term dynamic microenvironment. Results demonstrate that the vertically programmed substrates provide the most suitable dynamic microenvironment for PC12 cells as both the differentiation and maturity are promoted. Overall, this work provides a strategy for creating a long-term dynamic microenvironment for regulating nerve-cell fate and will inspire the rational design of NGCs for the treatment of PNIs.

A Solvent-Templated Porous Liquid Crystal Elastomer with Tactile Sensation beyond Reversible Actuation toward Versatile Artificial Muscles.

Liquid crystal elastomers (LCEs), as a classical two-way shape-memory material, are good candidates for developing artificial muscles that mimic the contraction, expansion, or rotational behavior of natural muscles. However, biomimicry is currently focused more on the actuation functions of natural muscles dominated by muscle fibers, whereas the tactile sensing functions that are dominated by neuronal receptors and synapses have not been well captured. Very few studies have reported the sensing concept for LCEs, but the signals were still donated by macroscopic actuation, that is, variations in angle or length. Herein, we develop a conductive porous LCE (CPLCE) using a solvent (dimethyl sulfoxide (DMSO))-templated photo-cross-linking strategy, followed by carbon nanotube (CNT) incorporation. The CPLCE has excellent reversible contraction/elongation behavior in a manner similar to the actuation functions of skeletal muscles. Moreover, the CPLCE shows excellent pressure-sensing performance by providing real-time electrical signals and is capable of microtouch sensing, which is very similar to natural tactile sensing. Furthermore, macroscopic actuation and tactile sensation can be integrated into a single system. Proof-of-concept studies reveal that the CPLCE-based artificial muscle is sensitive to external touch while maintaining its excellent actuation performance. The CPLCE with tactile sensation beyond reversible actuation is expected to benefit the development of versatile artificial muscles and intelligent robots.

Predictive potential of preoperative Naples prognostic score-based nomogram model for the prognosis in surgical resected thoracic esophageal squamous cell carcinoma patients: A retrospective cohort study.

The present study aimed to establish an effective prognostic nomogram model based on the Naples prognostic score (NPS) for resectable thoracic esophageal squamous cell carcinoma (ESCC). A total of 277 patients with ESCC, who underwent standard curative esophagectomy and designated as study cohort, were retrospectively analyzed. The patients were divided into different groups, including NPS 0, NPS 1, NPS 2, and NPS 3 or 4 groups, for further analysis, and the results were validated in an external cohort of 122 ESCC patients, who underwent surgery at another cancer center. In our multivariate analysis of the study cohort showed that the tumor-node-metastasis (TNM) stage, systemic inflammation score, and NPS were the independent prognostic factors for the overall survival (OS) and progression-free survival (PFS) durations. In addition, the differential grade was also an independent prognostic factor for the OS in the patients with ESCC after surgery (all P < .05). The area under the curve of receiver operator characteristics for the PFS and OS prediction with systemic inflammation score and NPS were 0.735 (95% confidence interval [CI] 0.676-0.795, P < .001) and 0.835 (95% CI 0.786-0.884, P < .001), and 0.734 (95% CI 0.675-0.793, P < .001) and 0.851 (95% CI 0.805-0.896, P < .001), respectively. The above independent predictors for OS or PFS were all selected in the nomogram model. The concordance indices (C-indices) of the nomogram models for predicting OS and PFS were 0.718 (95% CI 0.681-0.755) and 0.669 (95% CI 0.633-0.705), respectively, which were higher than that of the 7th edition of American Joint Committee on Cancer TNM staging system [C-index 0.598 (95% CI 0.558-0.638) for OS and 0.586 (95% CI 0.546-0.626) for PFS]. The calibration curves for predicting the 5-year OS or PFS showed a good agreement between the prediction by nomogram and actual observation. In the external validation cohort, the nomogram discrimination for OS was better than that of the 7th edition of TNM staging systems [C-index: 0.697 (95% CI 0.639-0.755) vs 0.644 (95% CI 0.589-0.699)]. The calibration curves showed good consistency in predicting the 5-year survival between the actual observation and nomogram predictions. The decision curve also showed a higher potential of the clinical application of predicting the 5-years OS of the proposed nomogram model as compared to that of the 7th edition of TNM staging systems. The preoperative NPS-based nomogram model had a certain potential role for predicting the prognosis of ESCC patients.

Hybrid Hydrogels for Immunoregulation and Proangiogenesis through Mild Heat Stimulation to Accelerate Whole-Process Diabetic Wound Healing.

Intense and persistent oxidative stress, excessive inflammation, and impaired angiogenesis severely hinder diabetic wound healing. Bioactive hydrogel dressings with immunoregulatory and proangiogenic properties have great promise in treating diabetic wounds. However, the therapeutic effects of dressings always depend on drugs with side effects, expensive cytokines, and cell therapies. Herein, a novel dynamic borate-bonds crosslinked hybrid multifunctional hydrogel dressings with photothermal properties are developed to regulate the microenvironment of diabetic wound sites and accelerate the whole process of its healing without additional medication. The hydrogel is composed of phenylboronic acid-modified chitosan and hyaluronic acid (HA) crosslinked by tannic acid (TA) through borate bonds and Prussian blue nanoparticles (PBNPs) with photothermal response characteristics are embedded in the polymer networks. The results indicate hydrogels show inherent broad-spectrum antioxidative activities through the integrated interaction of borate bonds, TA, and PBNPs. Meanwhile, combined with the regulation of macrophage phenotype by HA, the inflammatory microenvironment of diabetic wounds is transformed. Moreover, the angiogenesis is then enhanced by the mild photothermal effect of PBNPs, followed by promoted epithelialization and collagen deposition. In summary, this hybrid hydrogel system accelerates all stages of wound repair through antioxidative stress, immunomodulation, and proangiogenesis, showing great potential applications in diabetic wound management.

In-situ-sprayed therapeutic hydrogel for oxygen-actuated Janus regulation of postsurgical tumor recurrence/metastasis and wound healing.

Surgery is the mainstay of treatment modality for malignant melanoma. However, the deteriorative hypoxic microenvironment after surgery is recognized as a stemming cause for tumor recurrence/metastasis and delayed wound healing. Here we design and construct a sprayable therapeutic hydrogel (HIL@Z/P/H) encapsulating tumor-targeted nanodrug and photosynthetic cyanobacteria (PCC 7942) to prevent tumor recurrence/metastasis while promote wound healing. In a postsurgical B16F10 melanoma model in female mice, the nanodrug can disrupt cellular redox homeostasis via the photodynamic therapy-induced cascade reactions within tumor cells. Besides, the photosynthetically generated O2 by PCC 7942 can not only potentiate the oxidative stress-triggered cell death to prevent local recurrence of residual tumor cells, but also block the signaling pathway of hypoxia-inducible factor 1α to inhibit their distant metastasis. Furthermore, the long-lasting O2 supply and PCC 7942-secreted extracellular vesicles can jointly promote angiogenesis and accelerate the wound healing process. Taken together, the developed HIL@Z/P/H capable of preventing tumor recurrence/metastasis while promoting wound healing shows great application potential for postsurgical cancer therapy.

Multifunctional Hydrogels for the Healing of Diabetic Wounds.

The healing of diabetic wounds is hindered by various factors, including bacterial infection, macrophage dysfunction, excess proinflammatory cytokines, high levels of reactive oxygen species, and sustained hypoxia. These factors collectively impede cellular behaviors and the healing process. Consequently, this review presents intelligent hydrogels equipped with multifunctional capacities, which enable them to dynamically respond to the microenvironment and accelerate wound healing in various ways, including stimuli -responsiveness, injectable self-healing, shape -memory, and conductive and real-time monitoring properties. The relationship between the multiple functions and wound healing is also discussed. Based on the microenvironment of diabetic wounds, antibacterial, anti-inflammatory, immunomodulatory, antioxidant, and pro-angiogenic strategies are combined with multifunctional hydrogels. The application of multifunctional hydrogels in the repair of diabetic wounds is systematically discussed, aiming to provide guidelines for fabricating hydrogels for diabetic wound healing and exploring the role of intelligent hydrogels in the therapeutic processes.

Charged Fibrous Dressing to Promote Diabetic Chronic Wound Healing.

Diabetic chronic wounds cause a significant amount of pain to patients because of their low cure rates and high recurrence rates. Traditional approaches to treating diabetic chronic wounds often involve the delivery of drugs or cytokines that regulate the microenvironment and eliminate bacterial infection in the wound area, but they are passive in controlling cell behaviors and may lead to drug resistance. Emerging drug-free wound treatments are important for convenient, effective, and safe treatment strategies. However, the current approaches cannot fully promote tissue regeneration or prevent bacterial infections. Here, the efficacy of a negatively charged fiber dressing in promoting diabetic chronic wound healing is investigated. The negatively charged fiber dressing can generate reactive oxygen species to inhibit bacterial reproduction with the assistance of ultrasound during the inflammatory phase. Furthermore, the dressing provides an electrostatic field that regulates cellular behavior during the inflammatory and proliferative phases. In particular, the dressing can promote fibroblast migration and induce macrophage polarization and neovascularization without any additional drugs. It is demonstrated that this strategy enables the healing of diabetic chronic wounds in a mouse model, achieving effective wound closure over a 12-day treatment cycle and providing a drug-free therapeutic strategy for diabetic chronic wound care.

Bioinspired thermadapt shape-memory polymer with light-induced reversible fluorescence for rewritable 2D/3D-encoding information carriers.

Fluorescent materials have attracted widespread attention for information encryption owing to their stimuli-responsive color-shifting. However, the 2D encoding of fluorescent images poses a risk of information leakage. Herein, inspired by the mimic octopus capable of camouflage by changing colors and shapes, we develop a thermadapt shape-memory fluorescent film (TSFF) for integrating 2D/3D encoding in one system. The TSFF is based on anthracene group with reversible photo-cross-linking and poly (ethylene-co-vinyl acetate) network with thermadapt shape-memory properties. The reversible photo-cross-linking of anthracene is accompanied by repeatable fluorescence-shifting and enables rewritable 2D encoding. Meanwhile, the thermadapt shape-memory properties not only enables the reconfiguration of the permanent shape for creating and erasing 3D patterns, i.e., rewritable 3D information, but also facilitates recoverable shape programming for 3D encoding. This rewritable 2D/3D encoding strategy can enhance information security because only designated inspectors can decode the information by providing sequential heating for shape recovery and UV exposure. Overall, TSFF capable of rewritable 2D/3D encoding will inspire the design of smart materials for high-security information carriers.

An integrated quorum quenching biocatalytic nanoplatform for synergistic chemo-photothermal eradication of P. aeruginosa biofilm infections.

Decontamination of biofilm-associated infections presents a significant challenge due to the physical and chemical barrier created by the formation of extracellular matrices. This barrier restricts the access of antibiotics to the bacterial communities within the biofilm and provides protection to the persister cells, potentially leading to antibiotic resistance. In this study, we have developed an integrated quorum quenching biocatalytic nanoplatform for the synergistic chemo-photothermal eradication of P. aeruginosa biofilm infections. Ciprofloxacin (Cip), a model antibiotic, was absorbed onto PDA NPs through π-π stacking. Additionally, acylase (AC) was immobilized on PDA NPs through Schiff base reaction and Michael addition, resulting in the formation of the biocatalytic nanoplatform (PDA-Cip-AC NPs). This biocatalytic nanoplatform was able to enzymatically degrade AHL signaling molecules, thus achieving efficient quorum quenching activity to prevent biofilm formation. Furthermore, the NIR light-triggered on-demand Ciprofloxacin release further enhanced the eradication of P. aeruginosa biofilm infections with a synergy of local hyperthermia. We envision that this integrated quorum quenching nanoplatform provides a reliable tool for combating P. aeruginosa biofilm infections. STATEMENT OF SIGNIFICANCE: An integrated quorum quenching biocatalytic nanoplatform has been developed for the eradication of P. aeruginosa biofilm infections. Quorum-sensing signals play a crucial role in modulating bacterial cell-to-cell communication, biofilm formation, and secretion of virulence factors. This biocatalytic nanoplatform efficiently degrades AHL signaling molecules, thereby blocking cell-to-cell communication and preventing biofilm formation. Additionally, local hyperthermia and on-demand Ciprofloxacin release were achieved through NIR irradiation, working synergistically to eradicate P. aeruginosa biofilm infections.

Renal Clearable Magnetic Nanoreporter for Colorimetric Urinalysis of Tumor.

The convenience and availability are of great significance for the early screening of cancer. Herein, a magnetic nanoreporter with renal clearable capability and activatable catalytic activity was developed for colorimetric urinalysis of tumors. The magnetic nanoreporters were prepared by loading 3.2 nm Fe3O4 nanoparticles (NPs) and glucose oxidase (GOD) into macrophage cell-derived microvesicles (MVs) through electroporation, and these compositions serve as renal clearable catalytic reporters, synergistic catalysts, and targeted delivery carriers, respectively. The magnetic nanoreporters can convert the H2O2 in the mildly acidic tumor microenvironment into hydroxyl radicals through the synergistic catalysis of Fe3O4 NPs and GOD. Then the MVs can be disintegrated by the radicals, and ultrasmall Fe3O4 NPs will be released from the MVs at the tumor site, enabling rapid clearance of the Fe3O4 NPs into urine and a direct colorimetric urinalysis of the tumor within 4 h. The magnetic nanoreporters had good biocompatibility, and the released Fe3O4 NPs were rapidly excreted from the body, avoiding the potential toxicity. We envision that the magnetic nanoreporters can be used for convenient and rapid cancer screening.

Selective inhibition of glycolysis in hepatic stellate cells and suppression of liver fibrogenesis with vitamin A-derivative decorated camptothecin micelles.

The persistent transformation of quiescent hepatic stellate cells (HSCs) into myofibroblasts (MFs) and the excessive proliferation of MF-HSCs in the liver contribute to the pathogenesis of liver fibrosis, cirrhosis, and liver cancer. Glycolysis inhibition of MF-HSCs can reverse their MF phenotype and suppress their abnormal expansion. Here, we have developed vitamin A-derivative (VA) decorated PEG-PCL polymeric micelles to encapsulate the labile and hydrophobic camptothecin (CPT) and direct its active attack on HSCs, selectively inhibiting of HIF-1α and cellular glycolysis, ultimately repressing hepatic fibrogenesis. The obtained micelles exhibited a good stability, biocompatibility, pH sensitivity, and exceptional HSC-targetability, allowing an efficient accumulation of their carried CPT in acutely and chronically injured livers. On their intracellular release of CPT specifically in MF-HSCs, these CPT micelles nicely inhibited the HIF-1α and a series of glycolytic players in MF-HSCs and prominently suppressed their proliferation and MF phenotypic characteristics. Accordingly, on in vitro administration to the mice challenged by CCl4 or subjected to bile duct ligation, these VA-decorated CPT micelles ameliorated the pathological symptoms of the livers, as evidenced by the significant reduction in serum levels of ALT and AST, infiltration of inflammatory cells, and collagen accumulation, the drastic down-regulation of multiple fibrotic genes, and the good recovery of attenuated hepatocyte CYP2E1 and lipogenesis regulator PPARγ. Overall, the CPT carried by VA-decorated PEG-PCL polymeric micelles can selectively inhibit the glycolysis and expansion of HSCs and thus suppress fibrogenesis, providing an original and effective approach for anti-fibrotic therapy. STATEMENT OF SIGNIFICANCE: Our work introduces an innovative antifibrotic drug system that is developed upon the active targeting of CPT and aims for the fate reversal of HSCs. Through HSC-targeted delivery achieved by PEG-PCL polymeric micelles decorated with vitamin A-derivatives, CPT significantly suppressed the expressions of HIF-1α and glycolytic enzymes in MF-HSCs, as well as their pathologic expansion in mouse livers. It effectively ameliorated chronic liver fibrosis in mice induced by CCl4 injection or BDL and restored the damaged liver structure and function. These compelling findings demonstrate the therapeutic potential of glycolytic HSC-targeting in combating fibrosis and related disorders and thus provide new promise for future clinical management of such prevalent and life-threatening conditions.

Shell-Sheddable Polymeric Micelles Alleviate Oxidative Stress and Inflammation for Enhanced Ischemic Stroke Therapy.

As a ROS scavenger, resveratrol exerts a neuroprotective effect by polarizing the M1 microglia to the anti-inflammatory M2 phenotype for ischemic stroke treatment. However, the obstruction of the blood-brain barrier (BBB) seriously impairs the efficacy of resveratrol. Herein, we develop a stepwise targeting nanoplatform for enhanced ischemic stroke therapy, which is fabricated by pH-responsive poly(ethylene glycol)-acetal-polycaprolactone-poly(ethylene glycol) (PEG-Acetal-PCL-PEG) and modified with cRGD and triphenylphosphine (TPP) on a long PEG chain and a short PEG chain, respectively. The as-designed micelle system features effective BBB penetration through cRGD-mediated transcytosis. Once entering the ischemic brain tissues and endocytosed by microglia, the long PEG shell can be detached from the micelles in the acidic lysosomes, subsequently exposing TPP to target mitochondria. Thus, the micelles can effectively alleviate oxidative stress and inflammation by enhanced delivery of resveratrol to microglia mitochondria, reversing the microglia phenotype through the scavenging of ROS. This work offers a promising strategy to treat ischemia-reperfusion injury.

Antigen-Capturing Dendritic-Cell-Targeting Nanoparticles for Enhanced Tumor Immunotherapy Based on Photothermal-Therapy-Induced In Situ Vaccination.

In situ vaccines have revolutionized immunotherapy as they can stimulate tumor-specific immune responses, with the cancer being the antigen source. However, the heterogeneity of tumor antigens and insufficient dendritic cells (DCs) activation result in low cancer immunogenicity and hence poor vaccine response. Herein, a new in situ vaccine composed of acid-responsive liposome-coated polydopamine (PDA) nanoparticles modified with mannose and loaded with resiquimod (R848) is designed to promote the efficacy of immunotherapy. The in situ vaccine can actively target the tumor site based on the decomposition of the liposome, while the PDA nanoparticles promote photothermal therapy and capture the immunogenic cell-death-induced tumor-associated antigens based on the adsorption effect of dopamine-mimetic mussels. The PDA nanoparticles, which are modified with a mannose ligand, target the DCs and release R848 for activated antigen presentation. As a result, the in situ vaccine not only effectively activates the maturation of the DCs but also significantly enhances their effect on cytotoxic T lymphocyte cells. Furthermore, the vaccine effectively inhibits the distant recurrence and metastasis of tumors via long-term immune memory effects. Therefore, the in situ vaccine provides a potential strategy for improving the efficacy of cancer immunotherapy.

Bacteria-Derived Outer-Membrane Vesicles Hitchhike Neutrophils to Enhance Ischemic Stroke Therapy.

The treatment of reperfusion injury after ischemic stroke remains unsatisfactory since the blood-brain barrier (BBB) prevents most neuroprotective agents from entering the brain. Here, a strategy is proposed based on bacteria-derived outer-membrane vesicle (OMV) hitchhiking on the neutrophils for enhanced brain delivery of pioglitazone (PGZ) to treat ischemic stroke. By encapsulating PGZ into OMV, the resulting OMV@PGZ nanoparticles inherit the functions associated with the bacterial outer membrane, making them ideal decoys for neutrophil uptake. The results show that OMV@PGZ simultaneously inhibits the activation of nucleotide oligomerization-like receptor protein 3 (NLRP3) inflammasomes and ferroptosis and reduces the reperfusion injury to exert a neuroprotective effect. Notably, the transcription factors Pou2f1 and Nrf1 of oligodendrocytes are identified for the first time to be involved in this process and promoted neural repair by single-nucleus RNA sequencing (snRNA-seq).

Conductive Nanofibers-Enhanced Microfluidic Device for the Efficient Capture and Electrical Stimulation-Triggered Rapid Release of Circulating Tumor Cells.

The effective detection and release of circulating tumor cells (CTCs) are of great significance for cancer diagnosis and monitoring. The microfluidic technique has proved to be a promising method for CTCs isolation and subsequent analysis. However, complex micro-geometries or nanostructures were often constructed and functionalized to improve the capture efficiency, which limited the scale-up for high-throughput production and larger-scale clinical applications. Thus, we designed a simple conductive nanofiber chip (CNF-Chip)-embedded microfluidic device with a herringbone microchannel to achieve the efficient and specific capture and electrical stimulation-triggered rapid release of CTCs. Here, the most used epithelial cell adhesion molecule (EpCAM) was selected as the representative biomarker, and the EpCAM-positive cancer cells were mainly studied. Under the effects of the nanointerface formed by the nanofibers with a rough surface and the herringbone-based high-throughput microfluidic mixing, the local topographic interaction between target cells and nanofibrous substrate in the microfluidic was synergistically enhanced, and the capture efficiency for CTCs was further improved (more than 85%). After capture, the sensitive and rapid release of CTCs (release efficiency above 97%) could be conveniently achieved through the cleavage of the gold-sulfur bond by applying a low voltage (-1.2 V). The device was successfully used for the effective isolation of CTCs in clinical blood samples from cancer patients, indicating the great potential of this CNF-Chip-embedded microfluidic device in clinical applications.

KCl Nanoparticles as Potential Inducer of Immunogenic Cell Death for Cancer Immunotherapy.

Immunogenic cell death (ICD) is a promising cancer immunotherapy by inducing antigen-presenting cell maturation. Many inorganic nanomodulators have been developed for cancer therapy via ion overload, and their ICD-inducing properties have also been explored for immunotherapy. Here, we report a potassium chloride nanoparticle (PCNP)-loaded poly(lactic-co-glycolic acid) nanoparticle coated with cancer cell membrane (PC@P-CCM) for cancer therapy. Through cancer cell membrane (CCM)-achieved surface functionalization, the homotypic targeting behaviors of PC@P-CCM are dramatically enhanced. Once internalized by cancer cells, the PC@P-CCM could be degraded in acidic lysosomes, thus releasing K+ and Cl- ions. These ions can change the osmotic pressure of cancer cells, causing a hypertonic state in the cancer cells in a short time and leading to the rupture and death of cancer cells. Furthermore, these ions can stimulate cancer cells to secrete adenosine triphosphate (ATP) and high mobility group box 1 (HMGB-1); meanwhile, calreticulin (CRT) showed increased presentation on the surface of cancer cells, which can further induce dendritic cell maturation and promote the immunotherapy. This work provides a new perspective on KCl nanoparticle-based cancer immunotherapy.

Tumor Microenvironment-Inspired Glutathione-Responsive Three-Dimensional Fibrous Network for Efficient Trapping and Gentle Release of Circulating Tumor Cells.

Detection of circulating tumor cells (CTCs) is important for early cancer diagnosis, prediction of postoperative recurrence, and individualized treatment. However, it is still challenging to achieve efficient capture and gentle release of CTCs from the complex peripheral blood due to their rarity and fragility. Herein, inspired by the three-dimensional (3D) network structure and high glutathione (GSH) level of the tumor microenvironment (TME), a 3D stereo (3D-G@FTP) fibrous network is developed by combining the liquid-assisted electrospinning method, gas foaming technique, and metal-polyphenol coordination interactions to achieve efficient trapping and gentle release of CTCs. Compared with the traditional 2D@FTP fibrous scaffold, the 3D-G@FTP fibrous network could achieve higher capture efficiency (90.4% vs 78.5%) toward cancer cells in a shorter time (30 min vs 90 min). This platform showed superior capture performance toward heterogeneous cancer cells (HepG2, HCT116, HeLa, and A549) in an epithelial cell adhesion molecule (EpCAM)-independent manner. In addition, the captured cells with high cell viability (>90.0%) could be gently released under biologically friendly GSH stimulus. More importantly, the 3D-G@FTP fibrous network could sensitively detect 4-19 CTCs from six kinds of cancer patients' blood samples. We expect this TME-inspired 3D stereo fibrous network integrating efficient trapping, broad-spectrum recognition, and gentle release will promote the development of biomimetic devices for rare cell analysis.

Multifunctional Liposomes Remodeling Tumor Immune Microenvironment for Tumor Chemoimmunotherapy.

In the treatment of solid tumors, the complex barriers composed of cancer-associated fibroblasts (CAFs) prevent drug delivery and T cells infiltration into tumor tissues. Although nanocarriers hold great prospects in drug delivery, fibrosis causes the biological barrier and immunosuppressive tumor microenvironment (ITM) that impairs the anti-tumor efficacy of nanocarriers. Here, a small dendritic macromolecule loaded with doxorubicin (PAMAM-ss-DOX) (DP) is synthesized and encapsulated into pH-responsive nanoliposome, together with adjuvant toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) and losartan (LOS). The pH-responsive liposome facilitates the simultaneous and effective delivery of DP, R848, and LOS, which can decompose and release these drugs under the acidic tumor microenvironment. The small sized DP (≈25 nm) with the ability to penetrate into tumor tissue and immunogenic cell death (ICD) can reverse the ITM and elicit immune response, which is equivalent to the effect of an in situ vaccine. Moreover, LOS reduces the activity of CAFs effectively, which can contribute to the infiltration of T cells. Therefore, this nano-platform provides a new therapeutic strategy for enhanced chemo-immunotherapy.

A Hierarchical Structured Fiber Device Remodeling the Acidic Tumor Microenvironment for Enhanced Cancer Immunotherapy.

The acidic microenvironment of tumors significantly reduces the anti-tumor effect of immunotherapy. Herein, a hierarchically structured fiber device is developed as a local drug delivery system for remodeling the acidic tumor microenvironment (TME) to improve the therapeutic effect of immunotherapy. Proton pump inhibitors in the fiber matrix can be sustainedly released to inhibit the efflux of intracellular H+ from tumor cells, resulting in the remodeling of the acidic TME. The targeted micelles and M1 macrophage membrane-coated nanoparticles in internal cavities of fiber can induce immunogenic cell death (ICD) of tumor cells and phenotypic transformation of tumor-associated macrophages (TAMs), respectively. The relief of the acidity in the TME further promotes ICD and the polarization of TAMs, alleviating the immunosuppressive microenvironment and synergistically enhancing the antitumor immune response. In vivo results reveal this local drug delivery system restores the pH value of TME from 6.8 to 7.2 and exhibit an excellent immunotherapeutic effect.