Direct Assembly of Bioactive Nanoparticles Constructed from Polyphenol-Nanoengineered Albumin.

Albumin nanoparticles are widely used in biomedicine due to their safety, low immunogenicity, and prolonged circulation. However, incorporating therapeutic molecules into these carriers faces challenges due to limited binding sites, restricting drug conjugation efficiency. We introduce a universal nanocarrier platform (X-UNP) using polyphenol-based engineering to incorporate phenolic moieties into albumin nanoparticles. Integration of catechol or galloyl groups significantly enhances drug binding and broadens the drug conjugation possibilities. Our study presents a library of X-UNP nanoparticles with improved drug-loading efficiency, achieving up to 96% across 10 clinically used drugs, surpassing conventional methods. Notably, ibuprofen-UNP nanoparticles exhibit a 5-fold increase in half-life compared with free ibuprofen, enhancing in vivo analgesic and anti-inflammatory effectiveness. This research establishes a versatile platform for protein-based nanosized materials accommodating various therapeutic agents in biotechnological applications.

Metal-Phenolic Nanocloaks on Cancer Cells Potentiate STING Pathway Activation for Synergistic Cancer Immunotherapy.

Due to the presence of natural neoantigens, autologous tumor cells hold great promise as personalized therapeutic vaccines. Yet autologous tumor cell vaccines require multi-step production that frequently leads to the loss of immunoreactive antigens, causing insufficient immune activation and significantly hampering their clinical applications. Herein, we introduce a novel whole-cell cancer vaccine by cloaking cancer cells with lipopolysaccharide-decorated manganese(II)-phenolic networks (MnTA nanocloaks) to evoke tumor-specific immune response for highly efficacious synergistic cancer immunotherapy. The natural polyphenols coordinate with Mn2+ and immediately adhere to the surface of individual cancer cells, thereby forming a nanocloak and encapsulating tumor neoantigens. Subsequent decoration with lipopolysaccharide induces internalization by dendritic cells, where Mn2+ ions are released in the cytosol, further facilitating the activation of the stimulator of the interferon genes (STING) pathway. Highly effective tumor suppression was observed by combining the nanocloaked cancer cell treatment with anti-programmed cell death ligand 1 (anti-PD-L1) antibodies-mediated immune checkpoint blockade therapy. Our work demonstrates a universal yet simple strategy to engineer a cell-based nanobiohybrid system for enhanced cancer immunotherapy.

Cell-Targeted Metal-Phenolic Nanoalgaecide in Hydroponic Cultivation to Enhance Food Sustainability.

The growing global population necessitates substantial increases in food production. Hydroponic cultivation systems afford a critical alternative for food sustainability and enable stable annual production regardless of the climatic and geographical variations. However, the overgrowth of harmful algal blooms significantly threatens the crop yield by competing with nutrition in the solution and producing contaminants. The conventional practice of algaecides fails to control algal proliferation due to the limited efficiency and food safety concerns. Nanopesticides can deliver active ingredients responsively to suppress crop diseases and offer solutions to current practical challenges and difficulties. Inspired by prospects of nanotechnology for agricultural applications, we have utilized natural polyphenols and copper ions (Cu2+ ions) to develop self-assembled nanoalgaecides referred to as CuBes. The nanoalgaecide attached to algal cells via phenolic surface interactions, enabling localized Cu2+ ion release. This cell-targeted delivery suppressed Chlorella vulgaris for over 30 days (99% inhibition). Transcriptomics revealed that the nanoalgaecide disrupted algal metabolism by downregulating photosynthesis and chlorophyll pathways. In a solar-illuminated plant factory, the nanoalgaecide showed higher algal inhibition and lettuce biosafety versus the commercial Kocide 3000. Notably, the use of nanoalgaecide can enhance the nutrient value of lettuces, which meets the daily supply of Cu for adults. By integrating smart nanotechnology design with selective delivery mechanisms, this metal-phenolic nanoalgaecide provides a nanoenabled solution for controlling harmful algal blooms in hydroponics to advance food production.

Supramolecular nanoarchitectonics of phenolic-based nanofiller for controlled diffusion of versatile drugs in hydrogels.

Drug-dependent design of hydrogels is currently required for engineering the controlled release of therapeutics, which is a major contributor to the technical challenges relating to the clinical translation of hydrogel-drug systems. Herein, by integrating supramolecular phenolic-based nanofillers (SPFs) into hydrogel microstructures we developed a facile strategy to endow a range of clinically relevant hydrogels with controlled release properties for diverse therapeutic agents. The assembly of multiscale SPF aggregates leads to tunable mesh size and multiple dynamic interactions between SPF aggregates and drugs, which relaxes the available choices of drugs and hydrogels. This simple approach allowed for the controlled release of 12 representative drugs evaluated with 8 commonly used hydrogels. Moreover, the anesthetic drug lidocaine was loaded into SPF-integrated alginate hydrogel and demonstrated sustained release for 14 days in vivo, validating the potential for long-term anesthesia in patients.

Customizable Supraparticles Constructed from Catechol-Terminated Molecular Building Blocks with Controllable Intermolecular Interactions.

Colloidal supraparticles integrated with multicomponent primary particles come with emerging or synergetic functionalities. However, achieving the functional customization of supraparticles remains a great challenge because of the limited options of building blocks with tailorability and functional extensibility. Herein, we developed a universal approach to construct customizable supraparticles with desired properties from molecular building blocks obtained by the covalent conjugation of catechol groups with a series of orthogonal functional groups. These catechol-terminated molecular building blocks can assemble into primary particles driven by various intermolecular interactions (i.e. metal-organic coordination, host-guest, and hydrophobic interactions), and then further assemble into supraparticles governed by catechol-mediated interfacial interactions. Our strategy enables the formation of supraparticles with diverse functionalities, such as dual-pH responsiveness, light-controllable permeability, and non-invasive fluorescence labeling of living cells. The ease with which these supraparticles can be fabricated, and the ability to tailor their chemical and physical properties through the choice of metals and orthogonal functional groups used, should enable a variety of applications.

Systemic Tumor Suppression via Macrophage-Driven Automated Homing of Metal-Phenolic-Gated Nanosponges for Metastatic Melanoma.

Cell-based therapies comprising the administration of living cells to patients for direct therapeutic activities have experienced remarkable success in the clinic, of which macrophages hold great potential for targeted drug delivery due to their inherent chemotactic mobility and homing ability to tumors with high efficiency. However, such targeted delivery of drugs through cellular systems remains a significant challenge due to the complexity of balancing high drug-loading with high accumulations in solid tumors. Herein, a tumor-targeting cellular drug delivery system (MAGN) by surface engineering of tumor-homing macrophages (Mφs) with biologically responsive nanosponges is reported. The pores of the nanosponges are blocked with iron-tannic acid complexes that serve as gatekeepers by holding encapsulated drugs until reaching the acidic tumor microenvironment. Molecular dynamics simulations and interfacial force studies are performed to provide mechanistic insights into the "ON-OFF" gating effect of the polyphenol-based supramolecular gatekeepers on the nanosponge channels. The cellular chemotaxis of the Mφ carriers enabled efficient tumor-targeted delivery of drugs and systemic suppression of tumor burden and lung metastases in vivo. The findings suggest that the MAGN platform offers a versatile strategy to efficiently load therapeutic drugs to treat advanced metastatic cancers with a high loading capacity of various therapeutic drugs.

Multifunctional Dual Cross-Linked Bioadhesive Patch with Low Immunogenic Response and Wet Tissues Adhesion.

The development of bioadhesives is an important, yet challenging task as seemingly mutually exclusive properties need to be combined in one material, that is, strong adhesion, water resistance, and high biocompatibility. Here, a biocompatible and biodegradable protein-based bioadhesive patch (PBP) with high adhesion strength and low immunogenic response is reported. PBP exists as a strong adhesion for biological surfaces, which is higher than some conventional bioadhesives (i.e., polyethylene glycol and fibrin). Robust adhesion and strength are realized through the removal of interfacial water and fast formation of multiple supramolecular interactions induced by metal ions. The PBP's high biocompatibility is evaluated and immunogenic response in vitro and in vivo is neglected. The strong adhesion on soft biological tissues qualifies the PBP as biomedical glue outperforming some commercial products for applications in hemostasis performance, accelerated wound healing, and sealing of defected organs, anticipating to be useful as a tissue adhesive and sealant.

Roles of immune microenvironment in the female reproductive maintenance and regulation: novel insights into the crosstalk of immune cells.

Female fertility decline is an accumulative consequence caused by complex factors, among them, the disruption of the immune profile in female reproduction stands out as a crucial contributor. Presently, the effects of immune microenvironment (IME) on the female reproductive process have attracted increasing attentions for their dynamic but precisive roles. Immunocytes including macrophages, dendritic cells, T cells, B cells and neutrophils, with diverse subpopulations as well as high plasticity functioned dynamically in the process of female reproduction through indirect intercellular communication via specific cytokine release transduced by molecular signal networks or direct cell-cell contact to maintain the stability of the reproductive process have been unveiled. The immune profile of female reproduction in each stage has also been meticulously unveiled. Especially, the application of single-cell sequencing (scRNA-seq) technology in this process reveals the distribution map of immune cells, which gives a novel insight for the homeostasis of IME and provides a research direction for better exploring the role of immune cells in female reproduction. Here, we provide an all-encompassing overview of the latest advancements in immune modulation within the context of the female reproductive process. Our approach involves structuring our summary in accordance with the physiological sequence encompassing gonadogenesis, folliculogenesis within the ovaries, ovulation through the fallopian tubes, and the subsequent stages of embryo implantation and development within the uterus. Our overarching objective is to construct a comprehensive portrayal of the immune microenvironment (IME), thereby accentuating the pivotal role played by immune cells in governing the intricate female reproductive journey. Additionally, we emphasize the pressing need for heightened attention directed towards strategies that focus on immune interventions within the female reproductive process, with the ultimate aim of enhancing female fertility.

Type 2 diabetes mellitus and the risk of abnormal spermatozoa: A Mendelian randomization study.

Abnormal spermatozoa can not only reduce the fertilization rate, but also prolong the natural conception time and even increase the risk of spontaneous miscarriage. Diabetes mellitus (DM) has become a major global health problem, and its incidence continues to rise, while affecting an increasing number of men in their reproductive years. Type 2 Diabetes Mellitus (T2DM), accounting for about 85-95% of DM, is closely related to the development of sperm. However, the exact association between T2DM and abnormal spermatozoa remains unclear. Herein, we designed a Two-sample Mendelian randomization (MR) study to explore the causal association between T2DM and abnormal spermatozoa risk in European population data which come from the GWAS summary datasets. We selected 9 single nucleotide polymorphisms (SNPs) of T2DM (exposure data) as instrumental variables (IVs), and then retrieved the suitable abnormal spermatozoa genome-wide association study (GWAS) data of European from Ieu Open GWAS Project database which includes 915 cases and 209,006 control as the outcome data. Our results indicate that strict T2DM might not result in a higher risk of abnormal spermatozoa genetically in Europeans (OR: 1.017, 95% confidence interval (CI): 0.771-1.342, p=0.902). Our findings demonstrate that only T2DM may not explain the relatively higher risk of abnormal spermatozoa in men with it in Europeans. In subsequent studies, more comprehensive and larger samples need to be studied to reveal the relationship and potential mechanism between T2DM and abnormal spermatozoa.

The association between vitamin D and uterine fibroids: A mendelian randomization study.

Uterine fibroids (UFs), the most common benign gynecological tumor, can bring severe negative impacts on a woman's life quality. Vitamin D, is thought to play an important role in regulating cell proliferation and differentiation. In recent years, several studies suggested that higher level of vitamin D has a negative effect on the occurrence of UFs, but the results of studies on the relationship between them are conflicting and further evidence needs to be studied. Here in, we used a two-sample Mendelian Randomization (2SMR) study to explore the causal relationship between genetically predicted vitamin D levels and the risk of UFs. The exposure data comes from a genome-wide association study (GWAS) summary dataset consisting of 441,291 individuals, which includes datasets from United Kingdom Biobank, FinnGen Biobank and the corresponding consortia. Single-nucleotide polymorphisms (SNPs) associated with vitamin D at a significant level of p < 5 × 10-8 and low linkage disequilibrium (LD) level (r2 < 0.01) were selected. The outcome data comes from a GWAS dataset of IEU analysis of United Kingdom Biobank phenotypes consisting of 7,122 UFs cases and 455,811 controls. Our inverse-variance weight (IVW) analysis results support the causal association of genetically predicted vitamin D with the risk of UFs (OR = 0.995,95% CI = 0.990-0.999, p = 0.024). In addition, heterogeneity and pleiotropy were not observed in statistical models. In summary, our results indicate that elevated serum vitamin D levels are in strong relationship with reduction of the risk of UFs, which indicates that the clinical treatment of UFs may have a new and excellent option.

Intratumoral synthesis of transformable metal-phenolic nanoaggregates with enhanced tumor penetration and retention for photothermal immunotherapy.

Rationale: Effective photothermal therapy (PTT) remains a great challenge due to the difficulties of delivering photothermal agents with both deep penetration and prolonged retention at tumor lesion spatiotemporally. Methods: Here, we report an intratumoral self-assembled nanostructured aggregate named FerH, composed of a natural polyphenol and a commercial iron supplement. FerH assemblies possess size-increasing dynamic kinetics as a pseudo-stepwise polymerization from discrete nanocomplexes to microscale aggregates. Results: The nanocomplex can penetrate deeply into solid tumors, followed by prolonged retention (> 6 days) due to the in vivo growth into nanoaggregates in the tumor microenvironment. FerH performs a targeting ablation of tumors with a high photothermal conversion efficiency (60.2%). Importantly, an enhanced immunotherapeutic effect on the distant tumor can be triggered when co-administrated with checkpoint-blockade PD-L1 antibody. Conclusions: Such a therapeutic approach by intratumoral synthesis of metal-phenolic nanoaggregates can be instructive to address the challenges associated with malignant tumors.

Engineering microparticles based on solidified stem cell secretome with an augmented pro-angiogenic factor portfolio for therapeutic angiogenesis.

Tissue (re)vascularization strategies face various challenges, as therapeutic cells do not survive long enough in situ, while the administration of pro-angiogenic factors is hampered by fast clearance and insufficient ability to emulate complex spatiotemporal signaling. Here, we propose to address these limitations by engineering a functional biomaterial capable of capturing and concentrating the pro-angiogenic activities of mesenchymal stem cells (MSCs). In particular, dextran sulfate, a high molecular weight sulfated glucose polymer, supplemented to MSC cultures, interacts with MSC-derived extracellular matrix (ECM) components and facilitates their co-assembly and accumulation in the pericellular space. Upon decellularization, the resulting dextran sulfate-ECM hybrid material can be processed into MIcroparticles of SOlidified Secretome (MIPSOS). The insoluble format of MIPSOS protects protein components from degradation, while facilitating their sustained release. Proteomic analysis demonstrates that MIPSOS are highly enriched in pro-angiogenic factors, resulting in an enhanced pro-angiogenic bioactivity when compared to naïve MSC-derived ECM (cECM). Consequently, intravital microscopy of full-thickness skin wounds treated with MIPSOS demonstrates accelerated revascularization and healing, far superior to the therapeutic potential of cECM. Hence, the microparticle-based solidified stem cell secretome provides a promising platform to address major limitations of current therapeutic angiogenesis approaches.

A single-cell nanocoating of probiotics for enhanced amelioration of antibiotic-associated diarrhea.

The gut microbiota represents a large community of microorganisms that play an important role in immune regulation and maintenance of homeostasis. Living bacteria receive increasing interest as potential therapeutics for gut disorders, because they inhibit the colonization of pathogens and positively regulate the composition of bacteria in gut. However, these treatments are often accompanied by antibiotic administration targeting pathogens. In these cases, the efficacy of therapeutic bacteria is compromised by their susceptibility to antibiotics. Here, we demonstrate that a single-cell coating composed of tannic acids and ferric ions, referred to as 'nanoarmor', can protect bacteria from the action of antibiotics. The nanoarmor protects both Gram-positive and Gram-negative bacteria against six clinically relevant antibiotics. The multiple interactions between the nanoarmor and antibiotic molecules allow the antibiotics to be effectively absorbed onto the nanoarmor. Armored probiotics have shown the ability to colonize inside the gastrointestinal tracts of levofloxacin-treated rats, which significantly reduced antibiotic-associated diarrhea (AAD) resulting from the levofloxacin-treatment and improved some of the pre-inflammatory symptoms caused by AAD. This nanoarmor strategy represents a robust platform to enhance the potency of therapeutic bacteria in the gastrointestinal tracts of patients receiving antibiotics and to avoid the negative effects of antibiotics in the gastrointestinal tract.

Self-assembly of nanomicelles with rationally designed multifunctional building blocks for synergistic chemo-photodynamic therapy.

Rationale: The combination of photosensitizers, oxygen supply agents, and adjuvant therapy drugs in a single nano-drug delivery system for photodynamic therapy (PDT) has been showing great promises to overcome the inherent challenges of PDT for tumor treatment. However, the complicated preparation of integrating multiple components hampers their further developments. Here, we describe a self-assembly nanomicelle with rationally designed building blocks, which shows a high efficiency of synergistic chemo-photodynamic therapy in the animal modal. Methods: The nanomicelle was prepared by a coordination-driven self-assembly based on a rationally designed ferrocene cyclopalladated compound coupled with photosensitizers and hyaluronic acid (referred to as FCP-Tph/HA). The morphology, targeting drug delivery, pharmacokinetics, hemolysis, and multimodal synergistic therapy of FCP-Tph/HA were investigated. Results: The formation of nanomicelles presents a low hemolysis rate and a prolonged blood circulation time. FCP-Tph/HA possesses an enhanced antitumor effect in vitro through the specific binding of HA to CD44 and combining chemotherapy with oxygen self-supplying PDT. Simultaneously, the nanomicelle facilitates a significantly improved antitumor efficacy (>90% tumor regression) on a breast cancer model in vivo. Conclusion: Our results present a modular self-assembled nanomicellar platform with synergistic chemo-photodynamic therapy for challenging PDT-based tumor treatment.

Natural polyphenol-based nanoengineering of collagen-constructed hemoperfusion adsorbent for the excretion of heavy metals.

Designing a hemoperfusion adsorbent for the excretion therapy of toxic heavy metals still remains a great challenge due to the biosafety risks of non-biological materials and the desired highly efficient removal capacity. Herein, inspired from the homeostasis mechanism of plants, natural polyphenols are integrated with collagen matrix to construct a polyphenol-functionalized collagen-based artificial liver (PAL) for heavy metals excretion and free radicals scavenging therapy. PAL presents high adsorption capacities for Cu2+, Pb2+, and UO22+ ions, up to 76.98 µmol g-1, 106.70 µmol g-1, and 252.48 µmol g-1, respectively. Remarkably, PAL possesses a high binding affinity for UO22+, Pb2+, and Cu2+ ions even in the complex serum environment with the presence of biologically-relevant ions (e.g., Mg2+, Ca2+ ions). Low hemolysis ratio (1.77%), high cell viability (> 85%), high plasma recalcification time (17.4 min), and low protein adsorption (1.02 µmol g-1) indicate outstanding biocompatibility of this material. This natural polyphenol/collagen-based fully bio-derived hemoperfusion adsorbent provides a novel and potentially applicable strategy for constructing a hemoperfusion adsorbent for heavy metal ions excretion therapy with efficiency and biosafety.

Skin-inspired gelatin-based flexible bio-electronic hydrogel for wound healing promotion and motion sensing.

Next generation tissue-engineered skin scaffolds promise to provide sensory restoration through electrical stimulation in addition to effectively rebuilding and repairing skin. The integration of real-time monitoring of the injury motion activities can fundamentally improve the therapeutic efficacy by providing detailed data to guide the clinical practice. Herein, a mechanically-flexible, electroactive, and self-healable hydrogels (MESGel) was engineered for the combinational function of electrically-stimulated accelerated wound healing and motion sensing. MESGel shows outstanding biocompatibility and multifunctional therapeutic properties including flexibility, self-healing characteristics, biodegradability, and bioelectroactivity. Moreover, MESGel shows its potential of being a novel flexible electronic skin sensor to record the injury motion activities. Comprehensive in vitro and in vivo experiments prove that MESGel can facilitate effective electrical stimulation, actively promoting proliferation in Chinese hamster lung epithelial cells and therefore can accelerate favorable epithelial biology during skin wound healing, demonstrating an effective therapeutic strategy for a full-thickness skin defect model and leading to new-type flexible bioelectronics.

Assessment of the antitumor activity of a cyclopalladated ferrocene compound assisted by a dual-targeting drug delivery system.

One cyclopalladated ferrocene compound CP was synthesized, which showed a good cell cytotoxicity. Assisted by a dual-targeting drug delivery system, the anticancer activity of CP to MDA-MB-468 remained unchanged, but the toxicity to non-tumorigenic cell line NIH3T3 was remarkably reduced. This provided a new path for the development of cyclopalladated ferrocene as an antitumor drug candidate.