Achieving Endo/Lysosomal Escape Using Smart Nanosystems for Efficient Cellular Delivery.

The delivery of therapeutic agents faces significant hurdles posed by the endo-lysosomal pathway, a bottleneck that hampers clinical effectiveness. This comprehensive review addresses the urgent need to enhance cellular delivery mechanisms to overcome these obstacles. It focuses on the potential of smart nanomaterials, delving into their unique characteristics and mechanisms in detail. Special attention is given to their ability to strategically evade endosomal entrapment, thereby enhancing therapeutic efficacy. The manuscript thoroughly examines assays crucial for understanding endosomal escape and cellular uptake dynamics. By analyzing various assessment methods, we offer nuanced insights into these investigative approaches' multifaceted aspects. We meticulously analyze the use of smart nanocarriers, exploring diverse mechanisms such as pore formation, proton sponge effects, membrane destabilization, photochemical disruption, and the strategic use of endosomal escape agents. Each mechanism's effectiveness and potential application in mitigating endosomal entrapment are scrutinized. This paper provides a critical overview of the current landscape, emphasizing the need for advanced delivery systems to navigate the complexities of cellular uptake. Importantly, it underscores the transformative role of smart nanomaterials in revolutionizing cellular delivery strategies, leading to a paradigm shift towards improved therapeutic outcomes.

Harnessing the Power of Stimuli-Responsive Nanoparticles as an Effective Therapeutic Drug Delivery System.

The quest for effective and reliable methods of delivering medications, with the aim of improving delivery of therapeutic agent to the intended location, has presented a demanding yet captivating field in biomedical research. The concept of smart drug delivery systems is an evolving therapeutic approach, serving as a model for directing drugs to specific targets or sites. These systems have been developed to specifically target and regulate the administration of therapeutic substances in a diverse array of chronic conditions, including periodontitis, diabetes, cardiac diseases, inflammatory bowel diseases, rheumatoid arthritis, and different cancers. Nevertheless, numerous comprehensive clinical trials are still required to ascertain both the immediate and enduring impacts of such nanosystems on human subjects. This review delves into the benefits of different drug delivery vehicles, aiming to enhance comprehension of their applicability in addressing present medical requirements. Additionally, it touches upon the current applications of these stimuli-reactive nanosystems in biomedicine and outlines future development prospects.

Magnetic-Responsive Carbon Nanotubes Composite Scaffolds for Chondrogenic Tissue Engineering.

The demand for engineered scaffolds capable of delivering multiple cues to cells continues to grow as the interplay between cell fate with microenvironmental and external cues is revealed. Emphasis has been given to develop stimuli-responsive scaffolds. These scaffolds are designed to sense an external stimulus triggering a specific response (e.g., change in the microenvironment, release therapeutics, etc.) and then initiate/modulate a desired biofunction. Here, magnetic-responsive carboxylated multi-walled carbon nanotubes (cMWCNTs) are integrated into 3D collagen/polylactic acid (PLA) scaffold via a reproducible filtration-based method. The integrity and biomechanical performance of the collagen/PLA scaffolds are preserved after cMWCNT integration. In vitro safety assessment of cMWCNT/collagen/PLA scaffolds shows neither cytotoxicity effects nor macrophage pro-inflammatory response, supporting further in vitro studies. The cMWCNT/collagen/PLA scaffolds enhance chondrocytes metabolic activity while maintaining high cell viability and extracellular matrix (i.e., type II collagen and aggrecan) production. Comprehensive in vitro study applying static and pulsed magnetic field on seeded scaffolds shows no specific cell response in dependence with the applied field. This result is independent of the presence or absence of cMWCNT into the collagen/PLA scaffolds. Taken together, these findings provide additional evidence of the benefits to exploit the CNTs outstanding properties in the design of stimuli-responsive scaffolds.

Development of ε-poly(L-lysine) carbon dots-modified magnetic nanoparticles and their applications as novel antibacterial agents.

Magnetic nanoparticles (MNPs) are widely applied in antibacterial therapy owing to their distinct nanoscale structure, intrinsic peroxidase-like activities, and magnetic behavior. However, some deficiencies, such as the tendency to aggregate in water, unsatisfactory biocompatibility, and limited antibacterial effect, hindered their further clinical applications. Surface modification of MNPs is one of the main strategies to improve their (bio)physicochemical properties and enhance biological functions. Herein, antibacterial ε-poly (L-lysine) carbon dots (PL-CDs) modified MNPs (CMNPs) were synthesized to investigate their performance in eliminating pathogenic bacteria. It was found that the PL-CDs were successfully loaded on the surface of MNPs by detecting their morphology, surface charges, functional groups, and other physicochemical properties. The positively charged CMNPs show superparamagnetic properties and are well dispersed in water. Furthermore, bacterial experiments indicate that the CMNPs exhibited highly effective antimicrobial properties against Staphylococcus aureus. Notably, the in vitro cellular assays show that CMNPs have favorable cytocompatibility. Thus, CMNPs acting as novel smart nanomaterials could offer great potential for the clinical treatment of bacterial infections.

Multistage-Responsive Dual-Enzyme Nanocascades for Synergistic Radiosensitization-Starvation Cancer Therapy.

Radiotherapy is a common cancer treatment approach in clinical practice, yet its efficacy has been restricted by tumor hypoxia. Nanomaterials-mediated systemic delivery of glucose oxidase (GOx) and catalase (CAT) or CAT-like nanoenzymes holds the potential to enhance tumor oxygenation. However, they face the challenge of intermediate (hydrogen peroxide [H2 O2 ]) escape during systemic circulation if the enzyme pair is not closely placed to largely decompose H2 O2 , leading to oxidative stress on normal tissues. In the present study, a oxygen-generating nanocascade, n(GOx-CAT)C7A , constructed by strategically placing an enzymatic cascade (GOx and CAT) within a polymeric coating rich in hexamethyleneimine (C7A) moieties, is reported. During blood circulation, C7A remains predominantly non-protonated , achieving prolonged blood circulation due to its low-fouling surface. Once n(GOx-CAT)C7A reaches the tumor site, the acidic tumor microenvironment (TME) induces protonation of C7A moieties, resulting in a positively charged surface for enhanced tumor transcytosis. Moreover, GOx and CAT are covalently conjugated into close spatial proximity (<10 nm) for effective H2 O2  elimination. As demonstrated by the in vivo results, n(GOx-CAT)C7A achieves effective tumor retention and oxygenation, potent radiosensitization and antitumor effects. Such a dual-enzyme nanocascade for smart O2  delivery holds great potential for enhancing the hypoxia-compromised cancer therapies.

Smart Magnetic Optical Antenna for Automatic Nanoalignment and Photon Beaming from Prepatterned Single Quantum Dot Nanospot.

We present a unidirectional dielectric optical antenna, which can be chemically synthesized and controlled by magnetic fields. By applying magnetic fields, we successfully aligned an optical antenna on a prepatterned quantum dot nanospot with accuracy better than 40 nm. It confined the fluorescence emission into a 16-degree wide beam and enhanced the signal by 11.8 times. Moreover, the position of the antenna, and consequently the beam direction, can be controlled by simply adjusting the direction of the magnetic fields. Theoretical analyses show that this magnetic alignment technique is stable and accurate, providing a new strategy for building high-performance tunable nanophotonic devices.

Bioengineered materials with selective antimicrobial toxicity in biomedicine.

Fungi and bacteria afflict humans with innumerous pathogen-related infections and ailments. Most of the commonly employed microbicidal agents target commensal and pathogenic microorganisms without discrimination. To distinguish and fight the pathogenic species out of the microflora, novel antimicrobials have been developed that selectively target specific bacteria and fungi. The cell wall features and antimicrobial mechanisms that these microorganisms involved in are highlighted in the present review. This is followed by reviewing the design of antimicrobials that selectively combat a specific community of microbes including Gram-positive and Gram-negative bacterial strains as well as fungi. Finally, recent advances in the antimicrobial immunomodulation strategy that enables treating microorganism infections with high specificity are reviewed. These basic tenets will enable the avid reader to design novel approaches and compounds for antibacterial and antifungal applications.

pH-Activatable Organic Nanoparticles for Efficient Low-Temperature Photothermal Therapy of Ocular Bacterial Infection.

Low-temperature photothermal therapy (PTT) systems constructed by integrating organic photothermal agents with other bactericidal components that initiate bacterial apoptosis at low hyperthermia possess a promising prospect. However, these multicomponent low-temperature PTT nanoplatforms have drawbacks in terms of the tedious construction process, suboptimal synergy effect of diverse antibacterial therapies, and high laser dose needed, compromising their biosafety in ocular bacterial infection treatment. Herein, a mild PTT nanotherapeutic platform is formulated via the self-assembly of a pH-responsive phenothiazinium dye. These organic nanoparticles with photothermal conversion efficiency up to 84.5% necessitate only an ultralow light dose of 36 J/cm2 to achieve efficient low-temperature photothermal bacterial inhibition at pH 5.5 under 650 nm laser irradiation. In addition, this intelligent mild photothermal nanoplatform undergoes negative to positive charge reversion in acid biofilms, exhibiting good penetration and highly efficient elimination of drug-resistant E. coli biofilms under photoirradiation. Further in vivo animal tests demonstrated efficient bacterial elimination and inflammatory mitigation as well as superior biocompatibility and biosafety of the photothermal nanoparticles in ocular bacterial infection treatment. Overall, this efficient single-component mild PTT system featuring simple construction processes holds great potential for wide application and clinical transformation.

Smart nanomaterials for cancer diagnosis and treatment.

Innovations in nanomedicine has guided the improved outcomes for cancer diagnosis and therapy. However, frequent use of nanomaterials remains challenging due to specific limitations like non-targeted distribution causing low signal-to-noise ratio for diagnostics, complex fabrication, reduced-biocompatibility, decreased photostability, and systemic toxicity of nanomaterials within the body. Thus, better nanomaterial-systems with controlled physicochemical and biological properties, form the need of the hour. In this context, smart nanomaterials serve as promising solution, as they can be activated under specific exogenous or endogenous stimuli such as pH, temperature, enzymes, or a particular biological molecule. The properties of smart nanomaterials make them ideal candidates for various applications like biosensors, controlled drug release, and treatment of various diseases. Recently, smart nanomaterial-based cancer theranostic approaches have been developed, and they are displaying better selectivity and sensitivity with reduced side-effects in comparison to conventional methods. In cancer therapy, the smart nanomaterials-system only activates in response to tumor microenvironment (TME) and remains in deactivated state in normal cells, which further reduces the side-effects and systemic toxicities. Thus, the present review aims to describe the stimulus-based classification of smart nanomaterials, tumor microenvironment-responsive behaviour, and their up-to-date applications in cancer theranostics. Besides, present review addresses the development of various smart nanomaterials and their advantages for diagnosing and treating cancer. Here, we also discuss about the drug targeting and sustained drug release from nanocarriers, and different types of nanomaterials which have been engineered for this intent. Additionally, the present challenges and prospects of nanomaterials in effective cancer diagnosis and therapeutics have been discussed.

Advanced materials foresight: research and innovation indicators related to advanced and smart nanomaterials.

Background: Advanced materials are most likely to bring future economic, environmental and social benefits. At the same time, they may pose challenges regarding their safety and sustainability along the entire lifecycle. This needs to be timely addressed by the stakeholders (industry, research, policy, funding and regulatory bodies). As part of a larger foresight project, this study aimed to identify areas of scientific research and technological development related to advanced materials, in particular advanced nanomaterials and the sub-group of smart nanomaterials. The study identified and collected data to build relevant research and innovation indicators and analyse trends, impact and other implications. Methods: This study consisted of an iterative process including a documentation phase followed by the identification, description and development of a set of core research and innovation indicators regarding scientific publications, EU projects and patents. The data was extracted mainly from SCOPUS, CORDIS and PATSTAT databases using a predefined search string that included representative keywords. The trends, distributions and other aspects reflected in the final version of the indicators were analysed, e.g. the number of items in a period of time, geographical distribution, organisations involved, categories of journals, funding programmes, costs and technology areas. Results: Generally, for smart nanomaterials the data used represent around 3.5% of the advanced nanomaterials data, while for each field analysed, they represent 4.4% for publications, 13% for projects and 1.1% for patents. The study shows current trends for advanced nanomaterials at a top-level information that can be further extended with sub-indicators. Generally, the results indicated a significant growth in research into advanced nanomaterials, including smart nanomaterials, in the last decade, leading to an increased availability of information. Conclusion: These indicators identify trends regarding scientific and technological achievements and represent an important element when examining possible impacts on society and policy implications associated to these areas.

Optimization of Hemoglobin Encapsulation within PLGA Nanoparticles and Their Investigation as Potential Oxygen Carriers.

Hemoglobin (Hb)-based oxygen carriers (HBOCs) display the excellent oxygen-carrying properties of red blood cells, while overcoming some of the limitations of donor blood. Various encapsulation platforms have been explored to prepare HBOCs which aim to avoid or minimize the adverse effects caused by the administration of free Hb. Herein, we entrapped Hb within a poly(lactide-co-glycolide) (PLGA) core, prepared by the double emulsion solvent evaporation method. We study the effect of the concentrations of Hb, PLGA, and emulsifier on the size, polydispersity (PDI), loading capacity (LC), and entrapment efficiency (EE) of the resulting Hb-loaded PLGA nanoparticles (HbNPs). Next, the ability of the HbNPs to reversibly bind and release oxygen was thoroughly evaluated. When needed, trehalose, a well-known protein stabilizer that has never been explored for the fabrication of HBOCs, was incorporated to preserve Hb's functionality. The optimized formulation had a size of 344 nm, a PDI of 0.172, a LC of 26.9%, and an EE of 40.7%. The HbNPs were imaged by microscopy and were further characterized by FTIR and CD spectroscopy to assess their chemical composition and structure. Finally, the ability of the encapsulated Hb to bind and release oxygen over several rounds was demonstrated, showing the preservation of its functionality.

Physically Switchable Antimicrobial Surfaces and Coatings: General Concept and Recent Achievements.

Bacterial environmental colonization and subsequent biofilm formation on surfaces represents a significant and alarming problem in various fields, ranging from contamination of medical devices up to safe food packaging. Therefore, the development of surfaces resistant to bacterial colonization is a challenging and actively solved task. In this field, the current promising direction is the design and creation of nanostructured smart surfaces with on-demand activated amicrobial protection. Various surface activation methods have been described recently. In this review article, we focused on the "physical" activation of nanostructured surfaces. In the first part of the review, we briefly describe the basic principles and common approaches of external stimulus application and surface activation, including the temperature-, light-, electric- or magnetic-field-based surface triggering, as well as mechanically induced surface antimicrobial protection. In the latter part, the recent achievements in the field of smart antimicrobial surfaces with physical activation are discussed, with special attention on multiresponsive or multifunctional physically activated coatings. In particular, we mainly discussed the multistimuli surface triggering, which ensures a better degree of surface properties control, as well as simultaneous utilization of several strategies for surface protection, based on a principally different mechanism of antimicrobial action. We also mentioned several recent trends, including the development of the to-detect and to-kill hybrid approach, which ensures the surface activation in a right place at a right time.

Comprehensive review on ultrasound-responsive theranostic nanomaterials: mechanisms, structures and medical applications.

The field of theranostics has been rapidly growing in recent years and nanotechnology has played a major role in this growth. Nanomaterials can be constructed to respond to a variety of different stimuli which can be internal (enzyme activity, redox potential, pH changes, temperature changes) or external (light, heat, magnetic fields, ultrasound). Theranostic nanomaterials can respond by producing an imaging signal and/or a therapeutic effect, which frequently involves cell death. Since ultrasound (US) is already well established as a clinical imaging modality, it is attractive to combine it with rationally designed nanoparticles for theranostics. The mechanisms of US interactions include cavitation microbubbles (MBs), acoustic droplet vaporization, acoustic radiation force, localized thermal effects, reactive oxygen species generation, sonoluminescence, and sonoporation. These effects can result in the release of encapsulated drugs or genes at the site of interest as well as cell death and considerable image enhancement. The present review discusses US-responsive theranostic nanomaterials under the following categories: MBs, micelles, liposomes (conventional and echogenic), niosomes, nanoemulsions, polymeric nanoparticles, chitosan nanocapsules, dendrimers, hydrogels, nanogels, gold nanoparticles, titania nanostructures, carbon nanostructures, mesoporous silica nanoparticles, fuel-free nano/micromotors.

Towards safe and sustainable innovation in nanotechnology: State-of-play for smart nanomaterials.

The European Green Deal, the European Commission's new Action Plan for a Circular Economy, the new European Industrial Strategy and the Chemicals Strategy for Sustainability launched in October 2020 are ambitious plans to achieve a sustainable, fair and inclusive European Union's economy. In line with the United Nations Sustainable Development Goals 2030, these policies require that any new material or product should be not only functional and cost-effective but also safe and sustainable to ensure compliance with regulation and acceptance by consumers. Nanotechnology is one of the technologies that could enable such a green growth. This paper focuses on advanced nanomaterials that actively respond to external stimuli, also known as 'smart nanomaterials', and which are already on the market or in the research and development phase for non-medical applications such as in agriculture, food, food packaging and cosmetics. A review shows that smart nanomaterials and enabled products may present new challenges for safety and sustainability assessment due to their complexity and dynamic behaviour. Moreover, existing regulatory frameworks, in particular in the European Union, are probably not fully prepared to address them. What is missing today is a systematic and comprehensive approach that allows for considering sustainability aspects hand in hand with safety considerations very early on at the material design stage. We call on innovators, scientists and authorities to further develop and promote the 'Safe- and Sustainable-by-Design' concept in nanotechnology and propose some initiatives to go into this direction.

Smart Nanomaterials for Biomedical Applications-A Review.

Recent advances in nanotechnology have forced the obtaining of new materials with multiple functionalities. Due to their reduced dimensions, nanomaterials exhibit outstanding physio-chemical functionalities: increased absorption and reactivity, higher surface area, molar extinction coefficients, tunable plasmonic properties, quantum effects, and magnetic and photo properties. However, in the biomedical field, it is still difficult to use tools made of nanomaterials for better therapeutics due to their limitations (including non-biocompatible, poor photostabilities, low targeting capacity, rapid renal clearance, side effects on other organs, insufficient cellular uptake, and small blood retention), so other types with controlled abilities must be developed, called "smart" nanomaterials. In this context, the modern scientific community developed a kind of nanomaterial which undergoes large reversible changes in its physical, chemical, or biological properties as a consequence of small environmental variations. This systematic mini-review is intended to provide an overview of the newest research on nanosized materials responding to various stimuli, including their up-to-date application in the biomedical field.

Integrin-Targeting Peptides for the Design of Functional Cell-Responsive Biomaterials.

Integrins are a family of cell surface receptors crucial to fundamental cellular functions such as adhesion, signaling, and viability, deeply involved in a variety of diseases, including the initiation and progression of cancer, of coronary, inflammatory, or autoimmune diseases. The natural ligands of integrins are glycoproteins expressed on the cell surface or proteins of the extracellular matrix. For this reason, short peptides or peptidomimetic sequences that reproduce the integrin-binding motives have attracted much attention as potential drugs. When challenged in clinical trials, these peptides/peptidomimetics let to contrasting and disappointing results. In the search for alternative utilizations, the integrin peptide ligands have been conjugated onto nanoparticles, materials, or drugs and drug carrier systems, for specific recognition or delivery of drugs to cells overexpressing the targeted integrins. Recent research in peptidic integrin ligands is exploring new opportunities, in particular for the design of nanostructured, micro-fabricated, cell-responsive, stimuli-responsive, smart materials.

Polycaprolactone nanofiber mats decorated with photoresponsive nanogels and silver nanoparticles: Slow release for antibacterial control.

Smart nanomaterials activated by light is one of the most exciting strategies to control the release of substances in varied environments. Here we developed a smart nanomaterial composed by a photoresponsive nanogel containing silver nanoparticles (AgNps) immobilized on the surface of biodegradable and biocompatible polycaprolactone (PCL) nanofibers mats produced by electrospinning. The AgNps are released from the nanogel and dispersed inside the nanofiber mats when this system is irradiated by light at 405 nm. This light excites the plasmonic band of the AgNps, which breaks the nanogel and, as a consequence, releases the AgNps on the nanofibers. Consequently, this AgNps release mechanism controls the propagation of silver ions by the application of light. Different configurations of antibacterial nanofibers mats, including neat PCL nanofibers and PCL nanofibers modified with AgNps-Nanogels and AgNps, excited by laser light at 405 nm, were investigated regarding antibacterial properties. The best result was achieved using PCL nanofiber mats functionalized with AgNps and AgNps-Nanogels after light exposure, which generated inhibition diameters of 2.6 ±â€¯0.3 mm and 1.8 ±â€¯0.5 mm for S. aureus and E. coli, respectively. The smart nanomaterial developed here is a promising material for clinical application as wound dressing activated by light.

Targeting Inflammation With Nanosized Drug Delivery Platforms in Cardiovascular Diseases: Immune Cell Modulation in Atherosclerosis.

Atherosclerosis (AS) is a disorder of large and medium-sized arteries; it consists in the formation of lipid-rich plaques in the intima and inner media, whose pathophysiology is mostly driven by inflammation. Currently available interventions and therapies for treating atherosclerosis are not always completely effective; side effects associated with treatments, mainly caused by immunodepression for anti-inflammatory molecules, limit the systemic administration of these and other drugs. Given the high degree of freedom in the design of nanoconstructs, in the last decades researchers have put high effort in the development of nanoparticles (NPs) formulations specifically designed for either drug delivery, visualization of atherosclerotic plaques, or possibly the combination of both these and other functionalities. Here we will present the state of the art of these subjects, the knowledge of which is necessary to rationally address the use of NPs for prevention, diagnosis, and/or treatment of AS. We will analyse the work that has been done on: (a) understanding the role of the immune system and inflammation in cardiovascular diseases, (b) the pathological and biochemical principles in atherosclerotic plaque formation, (c) the latest advances in the use of NPs for the recognition and treatment of cardiovascular diseases, (d) the cellular and animal models useful to study the interactions of NPs with the immune system cells.

Polymeric Nanocomposites and Nanocoatings for Food Packaging: A Review.

Special properties of the polymeric nanomaterials (nanoscale size, large surface area to mass ratio and high reactivity individualize them in food packaging materials. They can be processed in precisely engineered materials with multifunctional and bioactive activity. This review offers a general view on polymeric nanocomposites and nanocoatings including classification, preparation methods, properties and short methodology of characterization, applications, selected types of them used in food packaging field and their antimicrobial, antioxidant, biological, biocatalyst and so forth, functions.