An Overview of Nanoparticle Protein Corona Literature.

The protein corona forms spontaneously on nanoparticle surfaces when nanomaterials are introduced into any biological system/fluid. Reliable characterization of the protein corona is, therefore, a vital step in the development of safe and efficient diagnostic and therapeutic nanomedicine products. 2134 published manuscripts on the protein corona are reviewed and a down-selection of 470 papers spanning 2000-2021, comprising 1702 nanoparticle (NP) systems is analyzed. This analysis reveals: i) most corona studies have been conducted on metal and metal oxide nanoparticles; ii) despite their overwhelming presence in clinical practice, lipid-based NPs are underrepresented in protein corona research, iii) studies use new methods to improve reliability and reproducibility in protein corona research; iv) studies use more specific protein sources toward personalized medicine; and v) careful characterization of nanoparticles after corona formation is imperative to minimize the role of aggregation and protein contamination on corona outcomes. As nanoparticles used in biomedicine become increasingly prevalent and biochemically complex, the field of protein corona research will need to focus on developing analytical approaches and characterization techniques appropriate for each unique nanoparticle formulation. Achieving such characterization of the nano-bio interface of nanobiotechnologies will enable more seamless development and safe implementation of nanoparticles in medicine.

Nanomedicine in Healing Chronic Wounds: Opportunities and Challenges.

The poor healing associated with chronic wounds affects millions of people worldwide through high mortality rates and associated costs. Chronic wounds present three main problems: First, the absence of a suitable environment to facilitate cell migration, proliferation, and angiogenesis; second, bacterial infection; and third, unbalanced and prolonged inflammation. Unfortunately, current therapeutic approaches have not been able to overcome these main issues and, therefore, have limited clinical success. Over the past decade, incorporating the unique advantages of nanomedicine into wound healing approaches has yielded promising outcomes. Nanomedicine is capable of stimulating various cellular and molecular mechanisms involved in the wound microenvironment via antibacterial, anti-inflammatory, and angiogenetic effects, potentially reversing the wound microenvironment from nonhealing to healing. This review briefly discusses wound healing mechanisms and pathophysiology and then highlights recent findings regarding the opportunities and challenges of using nanomedicine in chronic wound management.

The Possible Role of Sex As an Important Factor in Development and Administration of Lipid Nanomedicine-Based COVID-19 Vaccine.

Nanomedicine has demonstrated a substantial role in vaccine development against severe acute respiratory syndrome coronavirus (SARS-CoV-2 and COVID-19). Although nanomedicine-based vaccines have now been validated in millions of individuals worldwide in phase 4 and tracking of sex-disaggregated data on COVID-19 is ongoing, immune responses that underlie COVID-19 disease outcomes have not been clarified yet. A full understanding of sex-role effects on the response to nanomedicine products is essential to building an effective and unbiased response to the pandemic. Here, we exposed model lipid nanoparticles (LNPs) to whole blood of 18 healthy donors (10 females and 8 males) and used flow cytometry to measure cellular uptake by circulating leukocytes. Our results demonstrated significant differences in the uptake of LNP between male and female natural killer (NK) cells. The results of this proof-of-concept study show the importance of recipient sex as a critical factor which enables researchers to better consider sex in the development and administration of vaccines for safer and more-efficient sex-specific outcomes.

Restoring Endogenous Repair Mechanisms to Heal Chronic Wounds with a Multifunctional Wound Dressing.

Current treatment of chronic wounds has been critically limited by various factors, including bacterial infection, biofilm formation, impaired angiogenesis, and prolonged inflammation. Addressing these challenges, we developed a multifunctional wound dressing-based three-pronged approach for accelerating wound healing. The multifunctional wound dressing, composed of nanofibers, functional nanoparticles, natural biopolymers, and selected protein and peptide, can target multiple endogenous repair mechanisms and represents a promising alternative to current wound healing products.

COVID-19: Nanomedicine Uncovers Blood-Clot Mystery.

Further complications associated with infection by severe acute respiratory syndrome coronavirus 2 (a.k.a. SARS-CoV-2) continue to be reported. Very recent findings reveal that 20-30% of patients at high risk of mortality from COVID-19 infection experience blood clotting that leads to stroke and sudden death. Timely assessment of the severity of blood clotting will be of enormous help to clinicians in determining the right blood-thinning medications to prevent stroke or other life-threatening consequences. Therefore, rapid identification of blood-clotting-related proteins in the plasma of COVID-19 patients would save many lives. Several nanotechnology-based approaches are being developed to diagnose patients at high risk of death due to complications from COVID-19 infections, including blood clots. This Perspective outlines (i) the significant potential of nanomedicine in assessing the risk of blood clotting and its severity in SARS-CoV-2 infected patients and (ii) its synergistic roles with advanced mass-spectrometry-based proteomics approaches in identifying the important protein patterns that are involved in the occurrence and progression of this disease. The combination of such powerful tools might help us understand the clotting phenomenon and pave the way for development of new diagnostics and therapeutics in the fight against COVID-19.

Advancing In Situ Analysis of Biomolecular Corona: Opportunities and Challenges in Utilizing Field-Flow Fractionation.

The biomolecular corona, a complex layer of biological molecules, envelops nanoparticles (NPs) upon exposure to biological fluids including blood. This dynamic interface is pivotal for the advancement of nanomedicine, particularly in areas of therapy and diagnostics. In situ analysis of the biomolecular corona is crucial, as it can substantially improve our ability to accurately predict the biological fate of nanomedicine and, therefore, enable development of more effective, safe, and precisely targeted nanomedicines. Despite its importance, the repertoire of techniques available for in situ analysis of the biomolecular corona is surprisingly limited. This tutorial review provides an overview of the available techniques for in situ analysis of biomolecular corona with a particular focus on exploring both the advantages and the limitations inherent in the use of field-flow fractionation (FFF) for in situ analysis of the biomolecular corona. It delves into how FFF can unravel the complexities of the corona, enhancing our understanding and guiding the design of next-generation nanomedicines for medical use.

Improved Methodology for Evaluating Nanomedicine Antibacterial Properties in Biological Fluids.

Accurate assessment of nanomedicines' antibacterial properties is pivotal for their effective use in both in vitro and in vivo settings. Conventional antibacterial activity assessment methods, involving bacterial coculture with compounds on agar plates, may not fully suit nanomedicines due to their susceptibility to alterations in physicochemical properties induced by biological fluids. Furthermore, these biological fluids might even enhance the bacterial growth. This study introduces a novel, rigorous, and reproducible methodology for evaluating nanomedicine antibacterial properties using cell culture media (i.e., DMEM-FBS10%). To assess the antibacterial activity of the nanoparticles in cell culture media, superparamagnetic iron oxide nanoparticles (SPIONs) were chosen as the model nanomedicine due to their clinical significance. A comparative analysis between the traditional and our proposed methods yielded contrasting outcomes, shedding light on the significant impact of biological fluids on nanoparticle antibacterial activities. While the conventional approach suggested the antibacterial effectiveness of SPIONs against Staphylococcus aureus, our innovative method unveiled a substantial increase in bacterial growth in the presence of biological fluids. More specifically, we found a significant increase in bacterial growth when exposed to bare SPIONs at various concentrations, while the formation of a protein corona on SPION surfaces could markedly reduce the observed bacterial growth compared to the control group. These findings underscore the necessity for more refined evaluation techniques that can better replicate the in vivo environment when studying the nanomedicine's antibacterial capabilities.

Investigating Inflammatory Markers in Wound Healing: Understanding Implications and Identifying Artifacts.

Understanding the complex interplay of pro-inflammatory and anti-inflammatory cytokines is crucial in the field of wound healing, as it holds the key to developing effective therapeutics. In the initial stages of wound healing, pro-inflammatory cytokines like IL-1ß, IL-6, TNF-α, and various chemokines play vital roles in recruiting cells for debris clearance and the recruitment of growth factors. Careful regulation and timely resolution of this early inflammation are essential for optimal wound repair. As the healing process progresses, anti-inflammatory proteins such as IL-10 and IL-4 become instrumental in facilitating the transition to later stages where pro-inflammatory cytokines promote angiogenesis and wound remodeling. This Perspective underscores the complexity of inflammatory cytokines in wound healing research and emphasizes the need for comprehensive and unbiased methodologies in their evaluation. For robust and reliable results in wound-healing research, a more holistic approach is necessary-one that considers the roles, interactions, and timing of biological molecules, alongside careful sampling and evaluation strategies.

Protein Corona Composition of Gold Nanocatalysts.

The interaction between nanoparticles (NPs) and biological environments is profoundly influenced by a stable, strongly adsorbed "hard" protein corona. This corona significantly determines the NPs' pharmacokinetics and biological destiny. Our study delves into the mechanisms by which colloidal Au nanocrystals that are synthesized electrochemically without surface-capping organic ligands, known as CNM-Au8, traverse the blood-brain barrier (BBB) and target human brain tissue for treating neurodegenerative disorders. We discovered that upon interaction with human plasma, CNM-Au8 gold nanocrystals (AuNCs) effectively attract a variety of crucial apolipoproteins, notably apolipoproteins E, to their surfaces. This interaction likely facilitates their passage through the BBB. Furthermore, the coronas of these AuNCs exhibit a substantial presence of albumin and a notable absence of opsonin-based proteins, contributing to prolonged blood circulation. These characteristics align well with the clinical performance observed for the CNM-Au8 NCs. This study highlights that AuNCs with intentionally engineered structures and surfactant-free surfaces can create a distinct protein corona composition. This finding holds significant promise for the development of advanced therapeutic agents aimed at combating neurodegenerative diseases.

Toxicity of nanomaterials.

Nanoscience has matured significantly during the last decade as it has transitioned from bench top science to applied technology. Presently, nanomaterials are used in a wide variety of commercial products such as electronic components, sports equipment, sun creams and biomedical applications. There are few studies of the long-term consequences of nanoparticles on human health, but governmental agencies, including the United States National Institute for Occupational Safety and Health and Japan's Ministry of Health, have recently raised the question of whether seemingly innocuous materials such as carbon-based nanotubes should be treated with the same caution afforded known carcinogens such as asbestos. Since nanomaterials are increasing a part of everyday consumer products, manufacturing processes, and medical products, it is imperative that both workers and end-users be protected from inhalation of potentially toxic NPs. It also suggests that NPs may need to be sequestered into products so that the NPs are not released into the atmosphere during the product's life or during recycling. Further, non-inhalation routes of NP absorption, including dermal and medical injectables, must be studied in order to understand possible toxic effects. Fewer studies to date have addressed whether the body can eventually eliminate nanomaterials to prevent particle build-up in tissues or organs. This critical review discusses the biophysicochemical properties of various nanomaterials with emphasis on currently available toxicology data and methodologies for evaluating nanoparticle toxicity (286 references).

Nanomedicine Technologies for Diagnosis and Treatment of Breast Cancer.

Breast cancer is one of the most common cancers in women worldwide, yet conventional treatments have several shortcomings, including low specificity, systemic toxicity, and drug resistance. Nanomedicine technologies provide a promising alternative while also overcoming the limitations posed by conventional therapies. This mini-Review highlights important signaling pathways related to occurrence and development of breast cancer and current breast cancer therapies, followed by an analysis of various nanomedicine technologies developed for diagnosis and treatment of breast cancers.

Chronic Wound Healing Models.

In this paper, we review and analyze the commonly available wound healing models reported in the literature and discuss their advantages and issues, considering their relevance and translational potential to humans. Our analysis includes different in vitro and in silico as well as in vivo models and experimental techniques. We further explore the new technologies in the study of wound healing to provide an all encompassing review of the most efficient ways to proceed with wound healing experiments. We revealed that there is not one model of wound healing that is superior and can give translatable results to human research. Rather, there are many different models that have specific uses for studying certain processes or stages of wound healing. Our analysis suggests that when performing an experiment to assess stages of wound healing or different therapies to enhance healing, one must consider not only the species that will be used but also the type of model and how this can best replicate the physiology or pathophysiology in humans.

The Issue of Reliability and Repeatability of Analytical Measurement in Industrial and Academic Nanomedicine.

The issue of reliability and repeatability of data in the nanomedicine literature is a growing concern among stakeholders. This perspective discusses the key differences between academia and industry in the reproducibility of data acquisition and protocols in the field of nanomedicine. We also discuss what academic researchers can learn from systems implemented in industry to standardize data acquisition and in which ways these can be efficiently adopted by the academic community.

The need for the development of discipline-specific approaches to address academic bullying.

Background: It is now well-documented that academic bullying, mainly driven by power differences, affects all disciplines and academic people with various positions (from students to senior faculty) of all levels of experience. Our aim is to probe whether academic bullying, in its specific forms, manifests differently across disciplines. Methods: We analyzed discipline-specific data from our global survey on academic bullying, which was collected since November 2019. The survey was a cross-sectional global study that was administered via Qualtrics. It reflects responses from 2122 individuals whose participation was solicited through various means including advertisements in Science and Nature magazines and the American Chemical Society. Findings: The main finding is that academic bullying does not affect all scientific fields equally. Our cross-sectional global survey of targets of academic bullying indicates that bullying behavior depended strongly on the scientific discipline. Specifically, our comparison of the three major scientific categories, including Applied Sciences, Natural Sciences, and Social Sciences revealed significant differences (p < 0.05) in four (out of ten) of the contextual behaviors. Further comparison of the bullying behavior among specific disciplines (e.g., Chemistry, Engineering, Life Sciences, Neuroscience, and Social Sciences) revealed significant differences (p < 0.05) in five of the contextual behaviors. We also noticed that, among the top five disciplines analyzed, respondents in Engineering experienced the highest rate of bullying behaviors. Interpretation: The variation in contextual bullying behavior across disciplines suggests the need for specific and nuanced training, monitoring, and actions by stakeholders in addressing academic bullying in a context-specific manner. Funding: None.

In situ monitoring of photo-crosslinking reaction of water-soluble bifunctional macromers using magnetic levitation.

Crosslinking is one of the fundamental phenomena in polymer science, which happens by forming covalent bonds or relatively short sequences of chemical bonds to join two polymer chains. Crosslinking and the subsequent volume shrinkage of monomers/macromers result in changes in their corresponding density which can be measured using density-based measurement techniques (e.g., dilatometry). Here, we demonstrate a method that allows in situ monitoring of photopolymerization of water-soluble bifunctional macromers using magnetic levitation (MagLev) system. We use a hydrophobic paramagnetic solution to monitor the photopolymerization of water-soluble polyethylene glycol diacrylate (PEGDA) as a model of bifunctional macromers using a ring MagLev system. Based on changes in levitation heights (densities) after illumination of blue light, we have successfully monitored the double bond conversion of PEGDA 700 macromers at various polymerization conditions. Our findings suggest that MagLev can be used as a new and complementary analytical technique for rapid screening of the photopolymerization reactions and measurement of conversions using changes in the levitation height of the macromers.

Importance of Standardizing Analytical Characterization Methodology for Improved Reliability of the Nanomedicine Literature.

Understanding the interaction between biological structures and nanoscale technologies, dubbed the nano-bio interface, is required for successful development of safe and efficient nanomedicine products. The lack of a universal reporting system and decentralized methodologies for nanomaterial characterization have resulted in a low degree of reliability and reproducibility in the nanomedicine literature. As such, there is a strong need to establish a characterization system to support the reproducibility of nanoscience data particularly for studies seeking clinical translation. Here, we discuss the existing key standards for addressing robust characterization of nanomaterials based on their intended use in medical devices or as pharmaceuticals. We also discuss the challenges surrounding implementation of such standard protocols and their implication for translation of nanotechnology into clinical practice. We, however, emphasize that practical implementation of standard protocols in experimental laboratories requires long-term planning through integration of stakeholders including institutions and funding agencies.

Mass Spectrometry, Structural Analysis, and Anti-Inflammatory Properties of Photo-Cross-Linked Human Albumin Hydrogels.

Albumin-based hydrogels offer unique benefits such as biodegradability and high binding affinity to various biomolecules, which make them suitable candidates for biomedical applications. Here, we report a non-immunogenic photocurable human serum-based (HSA) hydrogel synthesized by methacryloylation of human serum albumin by methacrylic anhydride (MAA). We used matrix-assisted laser desorption ionization-time-of-flight mass spectrometry, liquid chromatography-tandem mass spectrometry, as well as size exclusion chromatography to evaluate the extent of modification, hydrolytic and enzymatic degradation of methacrylated albumin macromer and its cross-linked hydrogels. The impacts of methacryloylation and cross-linking on alteration of inflammatory response and toxicity were evaluated in vitro using brain-derived HMC3 macrophages and Ex-Ovo chick chorioallantoic membrane assay. Results revealed that the lysines in HSA were the primary targets reacting with MAA, though modification of cysteine, threonine, serine, and tyrosine, with MAA was also confirmed. Both methacrylated HSA and its derived hydrogels were nontoxic and did not induce inflammatory pathways, while significantly reducing macrophage adhesion to the hydrogels; one of the key steps in the process of foreign body reaction to biomaterials. Cytokine and growth factor analysis showed that albumin-based hydrogels demonstrated anti-inflammatory response modulating cellular events in HMC3 macrophages. Ex-Ovo results also confirmed the biocompatibility of HSA macromer and hydrogels along with slight angiogenesis-modulating effects. Photocurable albumin hydrogels may be used as a non-immunogenic platform for various biomedical applications including passivation coatings.

Interdependency of influential parameters in therapeutic nanomedicine.

Introduction:Current challenges to successful clinical translation of therapeutic nanomedicine have discouraged many stakeholders, including patients. Significant effort has been devoted to uncovering the reasons behind the less-than-expected success, beyond failures or ineffectiveness, of therapeutic nanomedicine products (e.g. cancer nanomedicine). Until we understand and address the factors that limit the safety and efficacy of NPs, both individually and in combination, successful clinical development will lag.Areas covered:This review highlights the critical roles of interdependent factors affecting the safety and therapeutic efficacy of therapeutic NPs for drug delivery applications.Expert opinion:Deep analysis of the current nanomedical literature reveals ahistory of unanticipated complexity by awide range of stakeholders including researchers. In the manufacture of nanomedicines themselves, there have been persistent difficulties with reproducibility and batch-to-batch variation. The unanticipated complexity and interdependency of nano-bio parameters has delayed our recognition of important factors affecting the safety and therapeutic efficacy of nanomedicine products. These missteps have had many factors including our lack of understanding of the interdependency of various factors affecting the biological identity and fate of NPs and biased interpretation of data. All these issues could raise significant concern regarding the reproducibility- or even the validity- of past publications that in turn formed the basis of many clinical trials of therapeutic nanomedicines. Therefore, the individual and combined effects of previously overlooked factors on the safety and therapeutic efficacy of NPs need to be fully considered in nanomedicine reports and product development.

The role of sex as a biological variable in the efficacy and toxicity of therapeutic nanomedicine.

Males and females have physiological, hormonal, and genetic differences that can cause different responses to medicinal treatments. The role of sex in the pharmacokinetics and pharmacodynamics of drugs is well established in the literature. However, researchers have yet to robustly and consistently consider the impact of sex differences on the pharmacokinetics and pharmacodynamics of nanomedicine formulations when designing nanomedicine therapeutics and/or constructing clinical trials. In this review, we highlight the physiological and anatomical differences between sexes and discuss how these differences can influence the therapeutic efficacy, side effects, and drug delivery safety of nanomedicine products. A deep understanding of the effects of sex on nano-based drug delivery agents will robustly improve the risk assessment process, resulting in safer formulations, successful clinical translation, and improved therapeutic efficacies for both sexes.

Biomolecular Corona Affects Controlled Release of Drug Payloads from Nanocarriers.

Nanomedicine has been widely used for a wide range of biomedical applications including drug delivery. Although many factors including the physicochemical properties of nanoparticles (NPs) and the payload efficacy of nanocarriers have been thoroughly investigated, the crucial role of the biomolecular corona in drug delivery and the release efficacy of nanocarriers demands further attention. This review highlights not only the crucial importance of the biomolecular corona to the drug release capacity of various types of nanocarriers, but also its interference with drug release measurements. A full consideration of the effects of the biomolecular corona on the controlled release and drug delivery of nanocarriers will help researchers design safer and more efficient nanobased drug delivery systems.