Omics-Guided Insights into Nanoparticle Complexity and Neural Regeneration

Engineered nanomaterials (ENMs) have been developed for imaging, drug delivery, diagnosis, and clinical therapeutic purposes because of their outstanding physicochemical characteristics. However, the function and ultimate efficiency of nanomedicines remain unsatisfactory for clinical application, mainly because of our insufficient understanding of nanomaterial/nanomedicine-biology (nano-bio) interactions. The nonequilibrated, complex, and heterogeneous nature of the biological milieu inevitably influences the dynamic bioidentity of nanoformulations at each site (i.e., the interfaces at different biological fluids (biofluids), environments, or biological structures) of nano-bio interactions. The continuous interplay between a nanomedicine and the biological molecules and structures in the biological environments can, for example, affect cellular uptake or completely alter the designed function of the nanomedicine. Accordingly, the weak and strong driving forces at the nano-bio interface may elicit structural reconformation, decrease bioactivity, and induce dysfunction of the nanomaterial and/or redox reactions with biological molecules, all of which may elicit unintended and unexpected biological outcomes. In contrast, these driving forces also can be manipulated to mitigate the toxicity of ENMs or improve the targeting abilities of ENMs. Therefore, a comprehensive understanding of the underlying mechanisms of nano-bio interactions is paramount for the intelligent design of safe and effective nanomedicines. In this Account, we summarize our recent progress in probing the nano-bio interaction of nanomedicines, focusing on the driving force and redox reaction at the nano-bio interface, which have been recognized as the main factors that regulate the functions and toxicities of nanomedicines. First, we provide insight into the driving force that shapes the boundary of different nano-bio interfaces (including proteins, cell membranes, and biofluids), for instance, hydrophobic, electrostatic, hydrogen bond, molecular recognition, metal-coordinate, and stereoselective interactions that influence the different nano-bio interactions at each contact site in the biological environment. The physicochemical properties of both the nanoparticle and the biomolecule are varied, causing structure recombination, dysfunction, and bioactivity loss of proteins; correspondingly, the surface properties, biological functions, intracellular uptake pathways, and fate of ENMs are also influenced. Second, with the help of these driving forces, four kinds of redox interactions with reactive oxygen species (ROS), antioxidant, sorbate, and the prosthetic group of oxidoreductases are utilized to regulate the intracellular redox equilibrium and construct synergetic nanomedicines for combating bacteria and cancers. Three kinds of electron-transfer mechanisms are involved in designing nanomedicines, including direct electron injection, sorbate-mediated, and irradiation-induced processes. Finally, we discuss the factors that influence the nano-bio interactions and propose corresponding strategies to manipulate the nano-bio interactions for advancing nanomedicine design. We expect our efforts in understanding the nano-bio interaction and the future development of this field will bring nanomedicine to human use more quickly.

Polyphenols, a diverse group of phytochemicals abundant in plant-derived foods, are being increasingly recognized for their regulatory effects on inflammation and metabolic disorders. Their interaction with the gut microbiota (GM) is complex and bidirectional: Polyphenols influence microbial composition by promoting the growth of beneficial bacteria and inhibiting pathogenic strains, while gut microbes metabolize polyphenols into bioactive metabolites that enhance their bioavailability. This dynamic interaction has profound implications for host metabolism, inflammation regulation, and disease prevention. Polyphenol-rich dietary sources, such as tea, berries, grapes, and pomegranates, exert prebiotic-like effects by selectively enriching commensal bacteria, including Lactobacillus and Bifidobacterium spp., while downregulating harmful genera such as Clostridium. These compounds attenuate inflammatory responses through the modulation of intracellular signaling cascades, suppression of pro-inflammatory cytokines, and mitigation of oxidative stress via activation of anti-oxidant pathways. Despite growing evidence supporting the beneficial health effects of polyphenols and their microbiota-derived metabolites, further mechanistic and longitudinal studies are warranted to elucidate the specific pathways involved and to assess their long-term impact on human health. This review highlights the role of polyphenols and gut-associated metabolites on various inflammatory pathways and associated metabolic syndrome.

Gut microbiota as a central mediator in hydrogen gas-induced alleviation of colitis via TLR4/NF-κB and Nrf2 pathway regulation.

Event Abstract Back to Event Biomimetic interfaces to trigger tissue restoration Ennio Tasciotti1, Francesca Taraballi1, Alessandro Parodi1, Jonathan O. Martinez1, Silvia Minardi1, Naama E. Toledano Furman1, Roberto Molinaro1, Fernando Cabrera1, Laura Pandolfi1, Bruna Corradetti1, Ciro Chiappini1, Jeffrey Van Eps1, Anna Tampieri1 and Bradley K. Weiner1 1 Houston Methodist Research Institute, Regenerative Medicine, United States Introduction: Cells interact and locally interface with the surrounding environment at the macroscale (whole organ), microscale (tissue), and nanoscale (extracellular matrix). Advances in micro and nano-engineering allow the synthesis of materials with features that allow to control and direct cell behavior at multiple scales. By tuning the physical, chemical and biological properties of the materials to match those of native tissues and of cellular processes, we generated biomimetic platforms able to overcome the biological barriers involved in drug delivery and tissue repair. By using the design principles of biomimicry, we exploited the nano-bio interface as a way to negotiate the restoration of tissues function. Materials and Methods: We developed two main classes of biomimetic materials: implantables and injectables. In both cases we applied fabrication strategies based on use of biomaterials able to mimic the material-cell interface for composition, architecture, function, assembly, and biochemical environment. In fact, in the synthesis of our multi-functional platforms was performed using exclusively the components typically found in the body: cellular membranes, proteins, or natural extracellular components (minerals and sugars). Results and Discussion: To overcome the barriers encountered during systemic administration, we developed a drug delivery system comprised of purified leukocyte membranes grafted onto the surface of a biodegradable core (i.e., leuko-like vectors, LLV). The proteolipid material transferred to LLV functioned as a biomimetic camouflage that allowed the inhibition of opsonization and reticulo-endothelial internalization; promoted the increased adherence to inflamed vasculature (Fig 1A), and the activation of intracellular pathways that resulted in the avoidance of endolysosomal entrapment and an increase in vascular permeability (Fig 1B)[1]. To gain access to the cytosol and increase the delivery of biologically labile payloads (nucleic acids), we developed biodegradable nanoneedles capable of directing interfacing with the cytosol through the penetration of the cellular membrane (i.e., nanoinjection). This nano-bio interface did not induce any toxic response in the cell by prompting the rearrangement of the nuclear and plasma membrane (Fig 1C,D)[2],[3], and allowed the in vivo delivery of genes to locally trigger increased neovascularization2 (Fig 1E-G). In tissue regeneration we widely exploited the idea of actively targeting the stem cell niche using different routes. We mimicked the regenerative niche in pore size, stiffness and overall architecture (Fig 2 A, B, C)[4]. Using nanoengineering, we tuned the release profiles of the embedded growth factors to control their local concentration to resemble the kinetics observed in physiological conditions (Fig 2 D, E, F, H)[5],[6]. All these strategies were successfully applied to functionally regenerate both hard and soft tissues. Conclusion: Biomimetic nanomaterials represent a powerful solution to interact with cells and guide their ultimate fate. By engineering surfaces to bestow them with the ability to instruct cells towards a regenerative outcome we achieved superior functional recovery and therapeutic outcome through the activation of the natural processes of cell and tissue healing.

The escalating global burden of cancer, marked by high incidence and mortality, necessitates more effective therapeutic strategies. A major bottleneck in clinical translation is the long-standing reliance on subcutaneous tumor models, which fail to recapitulate the complex physiological and pathological features of human malignancies. These ectopic models lack organ-specific barriers-such as the prostatic capsule, cervicovaginal mucus, and dense desmoplastic stroma-and cannot reproduce authentic metastatic niches or immune heterogeneity. Consequently, this review advocates a paradigm shift toward orthotopic-TME-informed nanomedicine design. We systematically evaluate recent progress in nanotherapeutics across twelve major malignancies, categorized into three strategic domains: (i) barrier-penetrating platforms engineered to navigate organ-specific physical and biochemical constraints; (ii) metastasis-targeted delivery systems that exploit native lymphovascular pathways; and (iii) microenvironment-responsive mechanisms that adapt to localized stimuli such as hypoxia and acidity. By integrating data from a wide range of studies, we highlight how orthotopic models provide a more rigorous platform for assessing drug penetration and therapeutic efficacy than conventional subcutaneous models. Furthermore, we critically discuss existing challenges, including manufacturing scalability, the bio-nano interface, and long-term toxicological safety. Looking forward, we propose a strategic roadmap that emphasizes the use of patient-derived orthotopic xenografts (PDOX), multi-omics data integration, and the development of closed-loop adaptive nanosystems. By aligning nanomaterial properties with constraints inherent to the orthotopic microenvironment, this review aims to provide a blueprint for the next generation of precision oncology platforms that can successfully bridge the gap from bench to bedside.

Properties such as fluorescence, superparamagnetism, photothermal effects and surface plasmon resonance provided by several inorganic nanocrystals make them very valuable for applications in various fields of medical science and biotechnology. A better understanding of the interactions and the phenomena that occur on the surface of the nanocrystals in complex biological environments is essential for further advances in the design of effective and safe nanomedicines. The first part of this chapter is dedicated to the description of the interactions between the surface of nanocrystals and the biological environment (nano–bio interface). The influence of the properties of nanocrystals on the formation of the protein corona and its specificities is discussed for nanocrystals of diverse composition. The main characteristics of the ligands that are typically employed to modify the surface of the nanocrystals and to impart targeting, imaging and therapeutic functionalities, among others, are introduced and described. An updated overview of the most common strategies for surface functionalization and bioconjugation at the nanoscale is provided.

Neurodegeneration is a pathological condition that is associated with the loss of neuronal function and structure. In neurodegenerative diseases, mounting evidence indicates that neuroinflammation is a common factor that contributes to neuronal damage and neurodegeneration. Neuroinflammation is characterized by the activation of microglia, the neuroimmune cells of the central nervous system (CNS), which have been implicated as active contributors to neuronal damage. Glycan structure modification is defining the outcome of neuroinflammation and neuronal regeneration; moreover, the expression of galectins, a group of lectins that specifically recognize β-galactosides, has been proposed as a key factor in neuronal regeneration and modulation of the inflammatory response. Of the different galectins identified, galectin-1 stimulates the secretion of neurotrophic factors in astrocytes and promotes neuronal regeneration, whereas galectin-3 induces the proliferation of microglial cells and modulates cell apoptosis. Galectin-8 emerged as a neuroprotective factor, which, in addition to its immunosuppressive function, could generate a neuroprotective environment in the brain. This review describes the role of galectins in the activation and modulation of astrocytes and microglia and their anti- and proinflammatory functions within the context of neuroinflammation. Furthermore, it discusses the potential use of galectins as a therapeutic target for the inflammatory response and remodeling in damaged tissues in the central nervous system.

Growth cones are essential for neuronal pathfinding during embryonic development and again after injury, when they aid in neuronal regeneration. This study was aimed at investigating the role of kinases in the earliest events in neuronal regeneration, namely, the formation of new growth cones from injured neuronal processes. Neurites of identified snail neurons grown in vitro were severed, and the formation of growth cones was observed from the ends of such transected processes. Under control conditions, all neurites formed a new growth cone within 45 min of transection. In contrast, growth cone formation in the presence of a general kinase inhibitor, K252a, was significantly inhibited. Moreover, decreasing the phosphorylation state of neurites by activating protein phosphatases with C2-ceramide also reduced growth cone formation. Pharmacological analysis with specific kinase inhibitors suggested that targets of protein kinase C (PKC) and tyrosine kinase (PTK) phosphorylation control growth cone formation. Inhibition of PKC with calphostin C and cerebroside completely blocked growth cone formation, whereas the inhibition of PTK with erbstatin analog significantly reduced growth cone formation. In contrast, inhibitors of protein kinase A, protein kinase G, CaM-kinase II, myosin light-chain kinase, Rho kinase, and PI-3 kinase had little or no effect 45 min after transection. These results suggest that the transformation underlying the formation of a growth cone from an injured (transected) neurite stump is highly sensitive to the phosphorylation state of key target proteins. Therefore, injury-induced signaling events will determine the outcome of neuronal regeneration through their action on kinase and phosphatase activities.

Point-of-care diagnostic tools, such as lateral flow assays (LFAs), play a critical role in disease management and outbreak control. LFAs detect the presence of target antigens in disease-relevant biofluids, utilizing nanoparticles (termed detection probes) to produce colorimetric readouts. However, significant intra- and interpatient variation in the biochemical composition of biofluids has downstream consequences for assay performance. Robust LFAs must be able to function alongside such variability to produce reliable and reproducible test outcomes. Beyond this, biofluids (such as serum) contain significant amounts of proteins, which can interact with detection probes used in LFAs to form a protein corona. The consequences of protein corona formation on LFA performance are poorly understood. Using a model antigen-biofluid LFA (human epidermal growth factor receptor 2 (HER2) and human serum), we observed significant discrepancies in LFA performance when using conventional nanoparticle functionalization methods, including the use of generic, nonhuman protein blocking agents. To overcome these performance differences, we developed a methodology for Bionano interface Optimization for LFA Design (termed BOLD). The BOLD workflow employs mass spectrometry-based proteomics to characterize the native protein corona, followed by formation of an engineered corona to produce an optimized bionano interface. We identified a specific protein (kininogen-1, KNG1) that demonstrated negative interference, significantly reducing the observed LFA test line intensity. This experimental finding is complemented by Molecular Dynamics simulations, which probe the binding modes of KNG1 to platinum nanoparticles. Further, through the employment of an apolipoprotein engineered corona (apolipoprotein A1, B, and C3), a robust LFA was developed, increasing test line intensity and significantly reducing intersample variation (with over a 4-fold improvement in the coefficient of variation). Overall, the BOLD workflow presents a method for the rational optimization of detection probes in LFAs through the characterization of the bionano interface to produce robust LFAs.

Multidisciplinary Materials Research in KAIST Over the Last 50 Years

Quantum dots (QDs), including semiconductor (Cd-based and III-V), carbon/graphene, and emerging halide perovskite QDs, offer size-tunable, bright, and photostable optical signals, making them uniquely suited as nanoreporters for neurotransmitter sensing. This review surveys recent advances in QD chemistry and surface engineering, recognition strategies (aptamers, molecularly imprinted polymers, enzymes, and small-molecule ligands), and signal transduction modalities (photoluminescence quenching/turn-on, FRET, electrochemiluminescence, and photoelectrochemical detection). We emphasise integration at the bio-nano interface for clinically relevant, minimally invasive platforms such as microfluidic sampling, wearable patches, and implantable probes, and analyse the principal barriers to translation (toxicity, stability in aqueous/biofluids, selectivity vs. interferents, and quantitation). Finally, we highlight promising directions: multiplexed spectral coding, ratiometric and lifetime-based readouts, renal-clearable/biodegradable QDs, and hybrid QD-polymer platforms for continuous monitoring of neurochemical signatures in diagnostic settings.

Free-living planarian flatworms have a long history of experimental usage owing to their remarkable regenerative abilities1. Small fragments excised from these animals reform the original body plan following regeneration of missing body structures. For example if a 'trunk' fragment is cut from an intact worm, a new 'head' will regenerate anteriorly and a 'tail' will regenerate posteriorly restoring the original 'head-to-tail' polarity of body structures prior to amputation (Figure 1A). Regeneration is driven by planarian stem cells, known as 'neoblasts' which differentiate into ~30 different cell types during normal body homeostasis and enforced tissue regeneration. This regenerative process is robust and easy to demonstrate. Owing to the dedication of several pioneering labs, many tools and functional genetic methods have now been optimized for this model system. Consequently, considerable recent progress has been made in understanding and manipulating the molecular events underpinning planarian developmental plasticity2-9. The planarian model system will be of interest to a broad range of scientists. For neuroscientists, the model affords the opportunity to study the regeneration of an entire nervous system, rather than simply the regrowth/repair of single nerve cell process that typically are the focus of study in many established models. Planarians express a plethora of neurotransmitters10, represent an important system for studying evolution of the central nervous system11, 12 and have behavioral screening potential13, 14. Regenerative outcomes are amenable to manipulation by pharmacological and genetic apparoaches. For example, drugs can be screened for effects on regeneration simply by placing body fragments in drug-containing solutions at different time points after amputation. The role of individual genes can be studied using knockdown methods (in vivo RNAi), which can be achieved either through cycles of microinjection or by feeding bacterially-expressed dsRNA constructs8, 9, 15. Both approaches can produce visually striking phenotypes at high penetrance- for example, regeneration of bipolar animals16-21. To facilitate adoption of this model and implementation of such methods, we showcase in this video article protocols for pharmacological and genetic assays (in vivo RNAi by feeding) using the planarian Dugesia japonica.

Free-living planarian flatworms have a long history of experimental usage owing to their remarkable regenerative abilities1. Small fragments excised from these animals reform the original body plan following regeneration of missing body structures. For example if a 'trunk' fragment is cut from an intact worm, a new 'head' will regenerate anteriorly and a 'tail' will regenerate posteriorly restoring the original 'head-to-tail' polarity of body structures prior to amputation (Figure 1A).Regeneration is driven by planarian stem cells, known as 'neoblasts' which differentiate into ~30 different cell types during normal body homeostasis and enforced tissue regeneration. This regenerative process is robust and easy to demonstrate. Owing to the dedication of several pioneering labs, many tools and functional genetic methods have now been optimized for this model system. Consequently, considerable recent progress has been made in understanding and manipulating the molecular events underpinning planarian developmental plasticity2-9.The planarian model system will be of interest to a broad range of scientists. For neuroscientists, the model affords the opportunity to study the regeneration of an entire nervous system, rather than simply the regrowth/repair of single nerve cell process that typically are the focus of study in many established models. Planarians express a plethora of neurotransmitters10, represent an important system for studying evolution of the central nervous system11, 12 and have behavioral screening potential13, 14.Regenerative outcomes are amenable to manipulation by pharmacological and genetic apparoaches. For example, drugs can be screened for effects on regeneration simply by placing body fragments in drug-containing solutions at different time points after amputation. The role of individual genes can be studied using knockdown methods (in vivo RNAi), which can be achieved either through cycles of microinjection or by feeding bacterially-expressed dsRNA constructs8, 9, 15. Both approaches can produce visually striking phenotypes at high penetrance- for example, regeneration of bipolar animals16-21. To facilitate adoption of this model and implementation of such methods, we showcase in this video article protocols for pharmacological and genetic assays (in vivo RNAi by feeding) using the planarian Dugesia japonica.

Immune Cell-NSPC interactions: Friend or foe in CNS injury and repair?

Tissue engineering holds immense promise for repairing damaged tissues and organs, yet current approaches often fall short due to poor host integration, limited drug delivery precision, and scalability challenges. Recent developments in electrostimulation‐responsive biomaterials incorporating drug or growth factor‐loaded nanoparticles offer a novel path forward. However, a comprehensive review integrating these emerging strategies within a unified framework is lacking. This review uniquely synthesizes current advances in electroactive materials such as conductive polymers, hydrogels, and piezoelectric scaffolds, and their dynamic interactions with electrostimulation at the cellular and molecular levels. It highlights how the incorporation of nanoparticles such as iron oxide, silver, and carbon‐based enhances localized therapeutic delivery and regenerative outcomes. Unlike existing literature, this work provides a cross‐tissue perspective, covering applications in cardiac, bone, cartilage, skin, neural, and cancer tissue regeneration. It also critically analyses fabrication techniques, biocompatibility issues, and design strategies for clinical scalability. By integrating diverse findings, the review identifies key knowledge gaps and emerging trends including smart, responsive scaffolds and interdisciplinary approaches that are shaping the future of regenerative medicine. This comprehensive and forward‐looking review serves as a novel resource for researchers and clinicians aiming to translate electrostimulation‐responsive platforms into effective next‐generation therapeutic solutions.