Clinical Translation Of Nanomedicine Research Articles

Enhanced wound healing effects of nanoscale lipid-diclofenac conjugates

Cold burn wounds have protracted and destructive effects on the body, like contracture, hypertrophic scars, and necrosis. Around 6.5 million people in the US are affected by chronic wounds every year. Different approaches have been utilized to cure this ailment, including cell-based therapy, drug based therapy, and temporary wound dressings, but no single treatment has been effective. Therefore, researchers are constantly searching for alternative therapeutic options. The present study evaluated the effects of nanoscale lipid-diclofenac conjugate (NLDCs) on cold-induced burn wounds. After NLDCs preparation and characterization, the therapeutic potential of them were evaluated. NLDCs exhibited better cell migration (in vitro), wound regeneration which in turn showed enhanced wound healing potential compared to diclofenac (positive control). Cell migration and wound closure in vitro was monitored by scratch assay. In vivo, a cold burn wound model was developed by direct exposure of the dorsal rat skin to liquid nitrogen. NLDCs were subcutaneously injected after 15 min of burn wound induction. The gross macroscopic examination of wound tissues was performed at days 1, 4, 8, and 16. Wound regeneration was observed in control (untreated) and treated groups (diclofenac and NLDCs). The wound regeneration was subsequently assessed by histological, gene expression, and immunohistochemical analyses at the early (day 8) and late (day 16) phases of wound healing. Scratch assay exhibited enhanced cell migration towards scratch area in the treated groups compared to the control. Macroscopic examination revealed early scab formations at day 8 in treated groups, while complete regeneration was only observed in the NLDCs group at day 16. Histological findings showed enhanced regeneration of skin layers along with hair follicles in the NLDCs treated group, while increased neovascularization was noted in both the treated groups. Gene expression profile of wound healing mediators showed downregulation of inflammatory (IL-1β, IL-6, and TNF-α) and Pain (COX-2, YKL-40, and Substance-7) markers and upregulation of angiogenic and remodeling (VEGF, TGFβ, FGF, PDGF, MMP-9, and EGF) markers at respective time points. In conclusion, NLDCs are potential anti-inflammatory, pain relieving, and wound healing agents. Prospects; We are optimistic that the NLDCs development and their scale-up production may pave the way towards clinical translation of nanomedicine in the management of pain, inflammation, and wound complications.

Nanomedomics.

Nanomaterials have attractive physicochemical properties. A variety of nanomaterials such as inorganic, lipid, polymers, and protein nanoparticles have been widely developed for nanomedicine via chemical conjugation or physical encapsulation of bioactive molecules. Superior to traditional drugs, nanomedicines offer high biocompatibility, good water solubility, long blood circulation times, and tumor-targeting properties. Capitalizing on this, several nanoformulations have already been clinically approved and many others are currently being studied in clinical trials. Despite their undoubtful success, the molecular mechanism of action of the vast majority of nanomedicines remains poorly understood. To tackle this limitation, herein, this review critically discusses the strategy of applying multiomics analysis to study the mechanism of action of nanomedicines, named nanomedomics, including advantages, applications, and future directions. A comprehensive understanding of the molecular mechanism could provide valuable insight and therefore foster the development and clinical translation of nanomedicines.

Nanoscale Surface Topography of Polyethylene Glycol-Coated Nanoparticles Composed of Bottlebrush Block Copolymers Prolongs Systemic Circulation and Enhances Tumor Uptake.

Improving the performance of nanocarriers remains a major challenge in the clinical translation of nanomedicine. Efforts to optimize nanoparticle formulations typically rely on tuning the surface density and thickness of stealthy polymer coatings, such as poly(ethylene glycol) (PEG). Here, we show that modulating the surface topography of PEGylated nanoparticles using bottlebrush block copolymers (BBCPs) significantly enhances circulation and tumor accumulation, providing an alternative strategy to improve nanoparticle coatings. Specifically, nanoparticles with rough surface topography achieve high tumor cell uptake in vivo due to superior tumor extravasation and distribution compared to conventional smooth-surfaced nanoparticles based on linear block copolymers. Furthermore, surface topography profoundly impacts the interaction with serum proteins, resulting in the adsorption of fundamentally different proteins onto the surface of rough-surfaced nanoparticles formed from BBCPs. We envision that controlling the nanoparticle surface topography of PEGylated nanoparticles will enable the design of improved nanocarriers in various biomedical applications.

Nanomedicine Combats Drug Resistance in Lung Cancer.

Lung cancer is the second most prevalent cancer and the leading cause of cancer-related death worldwide. Surgery, chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy are currently available as treatment methods. However, drug resistance is a significant factor in the failure of lung cancer treatments. Novel therapeutics have been exploited to address complicated resistance mechanisms of lung cancer and the advancement of nanomedicine is extremely promising in terms of overcoming drug resistance. Nanomedicine equipped with multifunctional and tunable physiochemical properties in alignment with tumor genetic profiles can achieve precise, safe, and effective treatment while minimizing or eradicating drug resistance in cancer. Here, this work reviews the discovered resistance mechanisms for lung cancer chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy, and outlines novel strategies for the development of nanomedicine against drug resistance. This work focuses on engineering design, customized delivery, current challenges, and clinical translation of nanomedicine in the application of resistant lung cancer.

Anticancer Nanotherapeutics in Clinical Trials: The Work behind Clinical Translation of Nanomedicine

The ultimate goal of nanomedicine has always been the generation of translational technologies that can ameliorate current therapies. Cancer disease represented the primary target of nanotechnology applied to medicine, since its clinical management is characterized by very toxic therapeutics. In this effort, nanomedicine showed the potential to improve the targeting of different drugs by improving their pharmacokinetics properties and to provide the means to generate new concept of treatments based on physical treatments and biologics. In this review, we considered different platforms that reached the clinical trial investigation, providing an objective analysis about their physical and chemical properties and the working mechanism at the basis of their tumoritr opic properties. With this review, we aim to help other scientists in the field in conceiving their delivering platforms for clinical translation by providing solid examples of technologies that eventually were tested and sometimes approved for human therapy.

Nanomedicine-Enabled/Augmented Cell Pyroptosis for Efficient Tumor Nanotherapy.

The terrible morbidity and mortality of malignant tumors urgently require innovative therapeutics, especially for apoptosis-resistant tumors. Pyroptosis, a pro-inflammatory form of programmed cell death (PCD), is featured with pore formation in plasma membrane, cell swelling with giant bubbles, and leakage of cytoplasmic pro-inflammatory cytokines, which can remodel the tumor immune microenvironment by stimulating a "cold" tumor microenvironment to be an immunogenic "hot" tumor microenvironment, and consequently augment the therapeutic efficiency of malignant tumors. Benefiting from current advances in nanotechnology, nanomedicine is extensively applied to potentiate, enable, and augment pyroptosis for enhancing cancer-therapeutic efficacy and specificity. This review provides a concentrated summary and discussion of the most recent progress achieved in this emerging field, highlighting the nanomedicine-enabled/augmented specific pyroptosis strategy for favoring the construction of next-generation nanomedicines to efficiently induce PCD. It is highly expected that the further clinical translation of nanomedicine can be accelerated by inducing pyroptotic cell death based on bioactive nanomedicines.

Supramolecular engineering of cell membrane vesicles for cancer immunotherapy

The clinical translation of nanomedicines has been strongly hampered by the limitations of delivery vehicles, promoting scientists to search for novel nanocarriers. Although cell membrane-based delivery systems have attracted extensive attention, further functionalizations are urgently desired to augment their theranostic functions. We propose a cell-friendly supramolecular strategy to engineer cell membranes utilizing cyclodextrin-based host–guest molecular recognitions to fix the defects arising from chemical and genetic modifications. In this study, the supramolecular cell membrane vesicles (SCMVs) specifically accumulate in tumors, benefiting from tumor-homing capability and the enhanced permeability and retention effect. SCMVs co-delivering indocyanine green and an indoleamine 2,3-dioxygenase inhibitor effectively ablate tumors combining photodynamic therapy and immunotherapy. Driven by host–guest inclusion complexation, SCMVs successfully encapsulate resiquimod to repolarize tumor-associated macrophages into M1 phenotype, synergizing with immune checkpoint blockade therapy. This supramolecular engineering methodology based on noncovalent interactions presents a generalizable and cell-friendly tactic to develop living cell–originated nanomaterials for precise cancer therapy.

Smart pH-responsive polyhydralazine/bortezomib nanoparticles for remodeling tumor microenvironment and enhancing chemotherapy

The clinical translation of nanomedicines has been impeded by the unfavorable tumor microenvironment (TME), particularly the tortuous vasculature networks, which significantly influence the transport and distribution of nanomedicines into tumors. In this work, a smart pH-responsive bortezomib (BTZ)-loaded polyhydralazine nanoparticle (PHDZ/BTZ) is presented, which has a great capacity to augment the accumulation of BTZ in tumors by dilating tumor blood vessels via specific release of vasodilator hydralazine (HDZ). The Lewis acid-base coordination effect between the boronic bond of BTZ and amino of HDZ empowered PHDZ/BTZ nanoparticles with great stability and high drug loading contents. Once triggered by the acidic tumor environment, HDZ could be released quickly to remodel TME through tumor vessel dilation, hypoxia attenuation, and lead to an increased intratumoral BTZ accumulation. Additionally, our investigation revealed that this pH-responsive nanoparticle dramatically suppressed tumor growth, inhibited the occurrence of lung metastasis with fewer side effects and induced immunogenic cell death (ICD), thereby eliciting immune activation including massive cytotoxic T lymphocytes (CTLs) infiltration in tumors and efficient serum proinflammatory cytokine secretion compared with free BTZ treatment. Thus, with efficient drug loading capacity and potent immune activation, PHDZ nanoparticles exhibit great potential in the delivery of boronic acid-containing drugs aimed at a wide range of diseases.

Clinical translation of nanomedicines: Challenges, opportunities, and keys.

Despite the massive interest and recent developments in the field of nanomedicine, only a limited number of formulations have found their way to the clinics. This shortcoming reveals the challenges facing the clinical translation of this technology. In the current article, we summarize and evaluate the status, market situation, and clinical profiles of the reported nanomedicines, the shortcomings limiting their clinical translation, as well as some approaches designed to break through this barrier. Moreover, some emerging technologies that have the potential to compete with nanomedicines are highlighted. Lastly, we identify the key factors that should be considered in nanomedicine-related research to be clinically-translatable. These can be classified into five areas: rational design during the research and development stage, the recruitment of representative preclinical models, careful design of clinical trials, development of specific and uniform regulatory protocols, and calls for non-classic sponsorship. This new field of endeavor was firmly established during the last two decades and more in-depth progress is expected in the coming years.

Multi-modal molecular imaging maps the correlation between tumor microenvironments and nanomedicine distribution.

Gaining insight into the heterogeneity of nanoparticle drug distribution within tumors would improve both design and clinical translation of nanomedicines. There is little data showing the spatio-temporal behavior of nanomedicines in tissues as current methods are not able to provide a comprehensive view of the nanomedicine distribution, released drug or its effects in the context of a complex tissue microenvironment.Methods: A new experimental approach which integrates the molecular imaging and bioanalytical technologies MSI and IMC was developed to determine the biodistribution of total drug and drug metabolite delivered via PLA-PEG nanoparticles and to overlay this with imaging of the nanomedicine in the context of detailed tumor microenvironment markers. This was used to assess the nanomedicine AZD2811 in animals bearing three different pre-clinical PDX tumors.Results: This new approach delivered new insights into the nanoparticle/drug biodistribution. Mass spectrometry imaging was able to differentiate the tumor distribution of co-dosed deuterated non-nanoparticle-formulated free drug alongside the nanoparticle-formulated drug by directly visualizing both delivery approaches within the same animal or tissue. While the IV delivered free drug was uniformly distributed, the nanomedicine delivered drug was heterogeneous. By staining for multiple biomarkers of the tumor microenvironment on the same tumor sections using imaging mass cytometry, co-registering and integrating data from both imaging modalities it was possible to determine the features in regions with highest nanomedicine distribution. Nanomedicine delivered drug was associated with regions higher in macrophages, as well as more stromal regions of the tumor. Such a comparison of complementary molecular data allows delineation of drug abundance in individual cell types and in stroma.Conclusions: This multi-modal imaging solution offers researchers a better understanding of drug and nanocarrier distribution in complex tissues and enables data-driven drug carrier design.

Functional Choline Phosphate Lipids for Enhanced Drug Delivery in Cancer Therapy

Liposome formulations by zwitterionic lipids (e.g., phosphatidyl choline (PC)) have been widely applied in the clinical translation of nanomedicines. However, poor bioorthogonality in the PC lipid backbone and limited cellular uptake potency significantly impede the development of a therapeutic strategy. Herein, we synthesized a novel bioorthogonal zwitterionic lipid named choline phosphate (CP), with reversed PC charge orientation via a phospholane derivative ring-opening reaction. CP lipids can assemble into liposomes with excellent biocompatibility and stable physical and chemical properties similar to PC liposomes. Due to supramolecular ionic pair interactions with the cell membrane, doxorubicin (Dox)-loaded CP liposomes (CP-Dox) were preferentially taken up and accumulated in cells compared to PC-Dox, which significantly enhanced the cytotoxicity in cancer cells and inhibited tumor growth. Furthermore, we determined the bioorthogonality of the CP lipids by conjugating folate in situ using a “click” reaction, which showed specificity in targeting treatment for breast cancer. Our studies provide a new proof of concept that functional liposomes can be designed at the molecular level. We also expect that CP lipids may have potential in other applications, including biosensors, antifouling coatings, cell membrane mimetic engineering, and artificial cells.

Nanoprecipitation preparation of low temperature-sensitive magnetoliposomes

Lysolipid-containing thermosensitive liposomes (LTSL) have gained attention for triggered release of chemotherapeutics. Superparamagnetic iron oxide nanoparticles (SPION) offers multimodal imaging and hyperthermia therapy opportunities as a promising theranostic agent. Combining LTSL with SPION may further enhance their performance and functionality of LTSL. However, a major challenge in clinical translation of nanomedicine is the poor scalability and complexity of their preparation process. Exploiting the nature of self-assembly, nanoprecipitation is a simple and scalable technique for preparing liposomes. Herein, we developed a novel SPION-incorporated lysolipid-containing thermosensitive liposome (mLTSL10) formulation using nanoprecipitation. The formulation and processing parameters were carefully designed to ensure high reproducibility and stability of mLTSL10. The effect of solvent, aqueous-to-organic volume ratio, SPION concentration on the mLTSL10 size and dispersity was investigated. mLTSL10 were successfully prepared with a small size (∼100 nm), phase transition temperature at around 42 °C, and high doxorubicin encapsulation efficiency. Indifferent from blank LTSL, we demonstrated that mLTSL10 combining the functionality of both LTSL and SPION can be successfully prepared using a scalable nanoprecipitation approach.

Developing New Cancer Nanomedicines by Repurposing Old Drugs

AbstractThe high morbidity and mortality of cancer requires innovative therapeutics. Very recently, several old drugs approved by the U.S. Food and Drug Administration (FDA) or currently undergoing clinical trials, such as 2‐deoxy‐d‐glucose, disulfiram, artemisinin, chloroquine, metformin, and aspirin, which have been extensively applied clinically for the treatment of other diseases with reliable evidence of biosafety, have been engineered into nanosystems for enhancing cancer therapy. These old drugs can cooperate with other components of nanosystems or the ambient biological environment, to favor tumor‐specific therapeutics by nontoxicity‐to‐toxicity transition. This Minireview provides a concentrated summary of the most recent progress made in this emerging field, highlighting the “old drugs, new uses” strategy for the construction of next‐generation nanomedicines. It is expected that the clinical translation of nanomedicines can be accelerated by repurposing old drugs to elevate cancer therapeutic efficacy and specificity.

Developing New Cancer Nanomedicines by Repurposing Old Drugs.

The high morbidity and mortality of cancer requires innovative therapeutics. Very recently, several old drugs approved by the U.S. Food and Drug Administration (FDA) or currently undergoing clinical trials, such as 2-deoxy-d-glucose, disulfiram, artemisinin, chloroquine, metformin, and aspirin, which have been extensively applied clinically for the treatment of other diseases with reliable evidence of biosafety, have been engineered into nanosystems for enhancing cancer therapy. These old drugs can cooperate with other components of nanosystems or the ambient biological environment, to favor tumor-specific therapeutics by nontoxicity-to-toxicity transition. This Minireview provides a concentrated summary of the most recent progress made in this emerging field, highlighting the "old drugs, new uses" strategy for the construction of next-generation nanomedicines. It is expected that the clinical translation of nanomedicines can be accelerated by repurposing old drugs to elevate cancer therapeutic efficacy and specificity.

Considerations for using optical clearing techniques for 3D imaging of nanoparticle biodistribution.

A key consideration in the clinical translation of nanomedicines is determining their in vivo biodistribution in preclinical studies, which is important for predicting and correlating therapeutic efficacy and safety. There are a number of techniques available for analyzing the in vivo biodistribution of nanoparticles, with each having its own advantages and limitations. However, conventional techniques are limited by their inability to image the three-dimensional (3D) association of nanoparticles with cells, vasculature and other biological structures in whole organs at a subcellular level. Recently, optical clearing techniques have been used to evaluate the biodistribution of nanoparticles by 3D organ imaging. Optical clearing is a procedure that is increasingly being used to improve the imaging of biological tissues, whereby light scattering substances are removed to better match the refractive indices of different tissue layers. The use of optical clearing techniques has the potential to transform the way we evaluate the biodistribution of new and existing nanomedicines, as it allows the visualization of the interaction of nanoparticles with the biological environment in intact tissues. This review will compare the main optical clearing techniques and will address the considerations for the use of these techniques to evaluate nanoparticle biodistribution.

Delivering the power of nanomedicine to patients today

The situation of the COVID-19 pandemic reminds us that we permanently need high-value flexible solutions to urgent clinical needs including simplified diagnostic technologies suitable for use in the field and for delivering targeted therapeutics. From our perspective nanotechnology is revealed as a vital resource for this, as a generic platform of technical solutions to tackle complex medical challenges. It is towards this perspective and focusing on nanomedicine that we take issue with Prof Park's recent editorial published in the Journal of Controlled Release. Prof. Park argued that in the last 15 years nanomedicine failed to deliver the promised innovative clinical solutions to the patients (Park, K. The beginning of the end of the nanomedicine hype. Journal of Controlled Release, 2019; 305, 221–222 [1]. We, the ETPN (European Technology Platform on Nanomedicine) [2], respectfully disagree. In fact, the more than 50 formulations currently in the market, and the recent approval of 3 key nanomedicine products (e. g. Onpattro, Hensify and Vyxeos), have demonstrated that the nanomedicine field is concretely able to design products that overcome critical barriers in conventional medicine in a unique manner, but also to deliver within the cells new drug-free therapeutic effects by using pure physical modes of action, and therefore make a difference in patients lives. Furthermore, the >400 nanomedicine formulations currently in clinical trials are expecting to bring novel clinical solutions (e.g. platforms for nucleic acid delivery), alone or in combination with other key enabling technologies to the market, including biotechnologies, microfluidics, advanced materials, biomaterials, smart systems, photonics, robotics, textiles, Big Data and ICT (information & communication technologies) more generally. However, we agree with Prof. Park that “ it is time to examine the sources of difficulty in clinical translation of nanomedicine and move forward “. But for reaching this goal, the investments to support clinical translation of promising nanomedicine formulations should increase, not decrease. As recently encouraged by EMA in its roadmap to 2025, we should create more unity through a common knowledge hub linking academia, industry, healthcare providers and hopefully policy makers to reduce the current fragmentation of the standardization and regulatory body landscape. We should also promote a strategy of cross-technology innovation, support nanomedicine development as a high value and low-cost solution to answer unmet medical needs and help the most promising innovative projects of the field to get better and faster to the clinic. This global vision is the one that the ETPN chose to encourage for the last fifteen years. All actions should be taken with a clear clinical view in mind, “ without any fanfare”, to focus “on what matters in real life”, which is the patient and his/her quality of life.This ETPN overview of achievements in nanomedicine serves to reinforce our drive towards further expanding and growing the maturity of nanomedicine for global healthcare, accelerating the pace of transformation of its great potential into tangible medical breakthroughs.

Clinical Translation of Nanomedicine and Biomaterials for Cancer Immunotherapy: Progress and Perspectives

AbstractAdvances in immuno‐oncology have significantly improved cancer therapy outcomes. Unfortunately, potent responses to immunotherapy have only been achieved in subsets of patients. Nanomedicines and biomaterials have enormous potential for making immunotherapy work better in more patients, which has been suggested by a large number of preclinical studies. However, it remains unclear whether and how these materials will really benefit cancer patients treated by immunotherapy. Therefore, reviewing current clinical studies on nanomedicines and biomaterials in immuno‐oncology may provide valuable information for future translation research. In this work, the clinical landscape of cancer immunotherapy involving nanomedicines and biomaterials, mainly Abraxane, Doxil, messenger ribonucleic acid (mRNA) nanovaccines, and a biomaterial scaffold‐supported autologous vaccine, is reviewed. Clinical results demonstrate the high potential of nano/biomaterials in immunotherapy, achieved by rationalized utilization of their targeted delivery and reduced toxicities/side effects. Future clinical translation in this field will likely benefit from designing rational combinations of nanomedicines and biomaterials with the right immunotherapeutics applied in the right patients/tumors, and this should be achieved with the help of immune biomarker analysis. By rationally utilizing the unique features and advantages of nanomedicines and biomaterials, they will highly impact patient care in combination with immunotherapy.

Dimerization-induced self-assembly of a redox-responsive prodrug into nanoparticles for improved therapeutic index

Although some formats of nanomedicines are now available for clinical use, the translation of new nanoparticles to the clinic remains a considerable challenge. Here, we describe a simple yet cost-effective strategy that converts a toxic drug, cabazitaxel, into a safe and effective nanomedicine. The strategy involves the ligation of drug molecules via a self-immolating spacer, followed by dimerization-induced self-assembly to assemble stable nanoparticles. Self-assembled cabazitaxel dimers could be further refined by PEGylation with amphiphilic polymers suitable for preclinical studies. This protocol enables the formation of systemically injectable nanoparticles (termed SNPs) with nearly quantitative entrapment efficiencies and exceptionally high drug loading (> 86%). In healthy mice, PEGylated SNPs show a favorable safety profile, with reduced systemic toxicity and negligible immunotoxicity. In two separate mouse xenograft models of cancer, administration of SNPs produces efficient antitumor activity with durable tumor suppression during therapeutic studies. Overall, this methodology opens up a practical and expedient route for the fabrication of clinically useful nanomedicines, transforming a hydrophobic and highly toxic drug into a systemic self-deliverable nanotherapy. Statement of SignificanceDespite the great progress in cancer nanomedicines, clinical translation of nanomedicines still remains a considerable challenge. In this study, we designed a self-assembling nanoplatform based on cabazitaxel dimer reversibly ligated via a bioactivatable linker. This approach enabled the generation of systemically injectable nanomedicines with quantitative entrapment efficiencies and exceptionally high drug loading (> 86%), which greatly obviates concerns about excipient-associated side effects. Self-assembled dimeric cabazitaxel exhibited a higher safety profile than free cabazitaxel and negligible immunotoxicity in animals. This is a practical and expedient example how the chemical ligation of a hydrophobic and highly toxic anticancer drug can be leveraged to create a self-assembling delivery nanotherapy which preserves inherent pharmacologic efficacy while reduces in vivo systemic and immune toxicity.

Nanomedicine Approaches for Advanced Diagnosis and Treatment of Atherosclerosis and Related Ischemic Diseases.

Cardiovascular diseases (CVDs) remain one of the major causes of mortality worldwide. In response to this and other worldwide health epidemics, nanomedicine has emerged as a rapidly evolving discipline that involves the development of innovative nanomaterials and nanotechnologies and their applications in therapy and diagnosis. Nanomedicine presents unique advantages over conventional medicines due to the superior properties intrinsic to nanoscopic therapies. Once used mainly for cancer therapies, recently, tremendous progress has been made in nanomedicine that has led to an overall improvement in the treatment and diagnosis of CVDs. This review elucidates the pathophysiology and potential targets of atherosclerosis and associated ischemic diseases. It may be fruitful to pursue future work in the nanomedicine-mediated treatment of CVDs based on these targets. A comprehensive overview is then provided featuring the latest preclinical and clinical outcomes in cardiovascular imaging, biomarker detection, tissue engineering, and nanoscale delivery, with specific emphasis on nanoparticles, nanostructured scaffolds, and nanosensors. Finally, the challenges and opportunities regarding the future development and clinical translation of nanomedicine in related fields are discussed. Overall, this review aims to provide a deep and thorough understanding of the design, application, and future development of nanomedicine for atherosclerosis and related ischemic diseases.

Molecular Mechanisms, Characterization Methods, and Utilities of Nanoparticle Biotransformation in Nanosafety Assessments.

It is a big challenge to reveal the intrinsic cause of a nanotoxic effect due to diverse branches of signaling pathways induced by engineered nanomaterials (ENMs). Biotransformation of toxic ENMs involving biochemical reactions between nanoparticles (NPs) and biological systems has recently attracted substantial attention as it is regarded as the upstream signal in nanotoxicology pathways, the molecular initiating event (MIE). Considering that different exposure routes of ENMs may lead to different interfaces for the arising of biotransformation, this work summarizes the nano-bio interfaces and dose calculation in inhalation, dermal, ingestion, and injection exposures to humans. Then, five types of biotransformation are shown, including aggregation and agglomeration, corona formation, decomposition, recrystallization, and redox reactions. Besides, the characterization methods for investigation of biotransformation as well as the safe design of ENMs to improve the sustainable development of nanotechnology are also discussed. Finally, future perspectives on the implications of biotransformation in clinical translation of nanomedicine and commercialization of nanoproducts are provided.