Phage-based delivery systems: engineering, applications, and challenges in nanomedicines.

Bacteriophages (phages) represent a unique category of viruses with a remarkable ability to selectively infect host bacteria, characterized by their assembly from proteins and nucleic acids. Leveraging their exceptional biological properties and modifiable characteristics, phages emerge as innovative, safe, and efficient delivery vectors. The potential drawbacks associated with conventional nanocarriers in the realms of drug and gene delivery include a lack of cell-specific targeting, cytotoxicity, and diminished in vivo transfection efficiency. In contrast, engineered phages, when employed as cargo delivery vectors, hold the promise to surmount these limitations and attain enhanced delivery efficacy. This review comprehensively outlines current strategies for the engineering of phages, delineates the principal types of phages utilized as nanocarriers in drug and gene delivery, and explores the application of phage-based delivery systems in disease therapy. Additionally, an incisive analysis is provided, critically examining the challenges confronted by phage-based delivery systems within the domain of nanotechnology. The primary objective of this article is to furnish a theoretical reference that contributes to the reasoned design and development of potent phage-based delivery systems.

Carbon Dots: Synthesis, Characterizations, and Recent Advancements in Biomedical, Optoelectronics, Sensing, and Catalysis Applications.

Carbon nanodots (CNDs), a fascinating carbon-based nanomaterial (typical size 2-10 nm) owing to their superior optical properties, high biocompatibility, and cell penetrability, have tremendous applications in different interdisciplinary fields. Here, in this Review, we first explore the superiority of CNDs over other nanomaterials in the biomedical, optoelectronics, analytical sensing, and photocatalysis domains. Beginning with synthesis, characterization, and purification techniques, we even address fundamental questions surrounding CNDs such as emission origin and excitation-dependent behavior. Then we explore recent advancements in their applications, focusing on biological/biomedical uses like specific organelle bioimaging, drug/gene delivery, biosensing, and photothermal therapy. In optoelectronics, we cover CND-based solar cells, perovskite solar cells, and their role in LEDs and WLEDs. Analytical sensing applications include the detection of metals, hazardous chemicals, and proteins. In catalysis, we examine roles in photocatalysis, CO2 reduction, water splitting, stereospecific synthesis, and pollutant degradation. With this Review, we intend to further spark interest in CNDs and CND-based composites by highlighting their many benefits across a wide range of applications.

Supramolecular Genome Editing: Targeted Delivery and Endogenous Activation of CRISPR/Cas9 by Dynamic Host-Guest Recognition.

We synthesize supramolecular poly(disulfide) (CPS) containing covalently attached cucurbit[7]uril (CB[7]), which is exploited not only as a carrier to deliver plasmid DNA encoding destabilized Cas9 (dsCas9), but also as a host to include trimethoprim (TMP) by CB[7] moieties through the supramolecular complexation to form TMP@CPS/dsCas9. Once the plasmid is transfected into tumor cells by CPS, the presence of polyamines can competitively trigger the decomplexation of TMP@CPS, thereby displacing and releasing TMP from CB[7] to stabilize dsCas9 that can target and edit the genomic locus of PLK1 to inhibit the growth of tumor cells. Following the systemic administration of TMP@CPS/dsCas9 decorated with hyaluronic acid (HA), tumor-specific editing of PLK1 is detected due to the elevated polyamines in tumor microenvironment, greatly minimizing off-target editing in healthy tissues and non-targeted organs. As the metabolism of polyamines is dysregulated in a wide range of disorders, this study offers a supramolecular approach to precisely control CRISPR/Cas9 functions under particular pathological contexts.

Biomedical application of metal-organic frameworks (MOFs) in cancer therapy: Stimuli-responsive and biomimetic nanocomposites in targeted delivery, phototherapy and diagnosis.

The nanotechnology is an interdisciplinary field that has become a hot topic in cancer therapy. Metal-organic frameworks (MOFs) are porous materials and hybrid composites consisted of organic linkers and metal cations. Despite the wide application of MOFs in other fields, the potential of MOFs for purpose of cancer therapy has been revealed by the recent studies. High surface area and porosity, significant drug loading and encapsulation efficiency are among the benefits of using MOFs in drug delivery. MOFs can deliver genes/drugs with selective targeting of tumor cells that can be achieved through functionalization with ligands. The photosensitizers and photo-responsive nanostructures including carbon dots and gold nanoparticles can be loaded in/on MOFs to cause phototherapy-mediated tumor ablation. The immunogenic cell death induction and increased infiltration of cytotoxic CD8+ and CD4+ T cells can be accelerated by MOF platforms in providing immunotherapy of tumor cells. The stimuli-responsive MOF platforms responsive to pH, redox, enzyme and ion can accelerate release of therapeutics in tumor site. Moreover, MOF nanocomposites can be modified ligands and green polymers to improve their selectivity and biocompatibility for cancer therapy. The application of MOFs for the detection of cancer-related biomarkers can participate in the early diagnosis of patients.

Chitosan-functionalized bioplatforms and hydrogels in breast cancer: immunotherapy, phototherapy and clinical perspectives.

Breast cancer is the most common and malignant tumor among women. Chitosan (CS)-based nanoparticles have been introduced into breast cancer therapy as a way to increase the targeted delivery of drugs and genes to the tumor site. CS nanostructures suppress tumorigenesis by enhancing both the targeted delivery of cargo (drug and gene) and its accumulation in tumor cells. The tumor cells internalize CS-based nanoparticles through endocytosis. Moreover, chitosan nanocarriers can also induce phototherapy-mediated tumor ablation. Smart and multifunctional types of CS nanoparticles, including pH-, light- and redox-responsive nanoparticles, can be used to improve the potential for breast cancer removal. In addition, the acceleration of immunotherapy by CS nanoparticles has also been achieved, and there is potential to develop CS-nanoparticle hydrogels that can be used to suppress tumorigenesis.

Graphene oxide nanoarchitectures in cancer therapy: Drug and gene delivery, phototherapy, immunotherapy, and vaccine development.

The latest advancements in oncology involves the creation of multifunctional nanostructures. The integration of nanoparticles into the realm of cancer therapy has brought about a transformative shift, revolutionizing the approach to addressing existing challenges and limitations in tumor elimination. This is particularly crucial in combating the emergence of resistance, which has significantly undermined the effectiveness of treatments like chemotherapy and radiotherapy. GO stands as a carbon-derived nanoparticle that is increasingly finding utility across diverse domains, notably in the realm of biomedicine. The utilization of GO nanostructures holds promise in the arena of oncology, enabling precise transportation of drugs and genetic material to targeted sites. GO nanomaterials offer the opportunity to enhance the pharmacokinetic behavior and bioavailability of drugs, with documented instances of these nanocarriers elevating drug accumulation at the tumor location. The GO nanostructures encapsulate genes, shielding them from degradation and facilitating their uptake within cancer cells, thereby promoting efficient gene silencing. The capability of GO to facilitate phototherapy has led to notable advancements in reducing tumor progression. By PDT and PTT combination, GO nanomaterials hold the capacity to diminish tumorigenesis. GO nanomaterials have the potential to trigger both cellular and innate immunity, making them promising contenders for vaccine development. Additionally, types of GO nanoparticles that respond to specific stimuli have been applied in cancer eradication, as well as for the purpose of cancer detection and biomarker diagnosis. Endocytosis serves as the mechanism through which GO nanomaterials are internalized. Given these advantages, the utilization of GO nanomaterials for tumor elimination comes highly recommended.

Hyaluronic acid-empowered nanotheranostics in breast and lung cancers therapy.

Nanomedicine application in cancer therapy is an urgency because of inability of current biological therapies for complete removal of tumor cells. The development of smart and novel nanoplatforms for treatment of cancer can provide new insight in tumor suppression. Hyaluronic acid is a biopolymer that can be employed for synthesis of smart nanostructures capable of selective targeting CD44-overexpressing tumor cells. The breast and lung cancers are among the most malignant and common tumors in both females and males that environmental factors, lifestyle and genomic alterations are among the risk factors for their pathogenesis and development. Since etiology of breast and lung tumors is not certain and multiple factors participate in their development, preventative measures have not been completely successful and studies have focused on developing new treatment strategies for them. The aim of current review is to provide a comprehensive discussion about application of hyaluronic acid-based nanostructures for treatment of breast and lung cancers. The main reason of using hyaluronic acid-based nanoparticles is their ability in targeting breast and lung cancers in a selective way due to upregulation of CD44 receptor on their surface. Moreover, nanocarriers developed from hyaluronic acid or functionalized with hyaluronic acid have high biocompatibility and their safety is appreciated. The drugs and genes used for treatment of breast and lung cancers lack specific accumulation at cancer site and their cytotoxicity is low, but hyaluronic acid-based nanostructures provide their targeted delivery to tumor site and by increasing internalization of drugs and genes in breast and lung tumor cells, they improve their therapeutic index. Furthermore, hyaluronic acid-based nanostructures can be used for phototherapy-mediated breast and lung cancers ablation. The stimuli-responsive and smart kinds of hyaluronic acid-based nanostructures such as pH- and light-responsive can increase selective targeting of breast and lung cancers.

Bioresponsive and multifunctional cyclodextrin-based non-viral nanocomplexes in cancer therapy: Building foundations for gene and drug delivery, immunotherapy and bioimaging.

The interest towards application of nanomaterials in field of cancer therapy is that the drawbacks of conventional therapies including chemoresistance, radio-resistance and lack of specific targeting of tumor cells can be solved by nanotechnology. Cyclodextrins (CDs) are amphiphilic cyclic oligosaccharides that can be present in three forms of α-, ß- and γ-CDs, and they can be synthesized from natural sources. The application of CDs in cancer shows an increasing trend due to benefits of these nanocomplexes in improving solubility and bioavailability of current bioactives and therapeutics for cancer. CDs are widely utilized in delivery of drugs and genes in cancer therapy, and by targeted delivery of these therapeutics into target site, they improve anti-proliferative and anti-cancer potential. The blood circulation time and tumor site accumulation of therapeutics can be improved using CD-based nanostructures. More importantly, the stimuli-responsive types of CDs including pH-, redox- and light-sensitive types can accelerate release of bioactive compound at tumor site. Interestingly, the CDs are able to mediate photothermal and photodynamic impact in impairing tumorigenesis in cancer, enhancing cell death and improving response to chemotherapy. In improving the targeting ability of CDs, their surface functionalization with ligands has been conducted. Moreover, CDs can be modified with green products such as chitosan and fucoidan, and they can be embedded in green-based nanostructures to suppress tumorigenesis. The internalization of CDs into tumor cells can occur through endocytosis and this can be clethrin-, caveolae- or receptor-mediated endocytosis. Furthermore, CDs are promising candidates in bioimaging, cancer cell and organelle imaging as well as isolating tumor cells. The main benefits of using CDs in cancer therapy including sustained and low release of drugs and genes, targeted delivery, bioresponsive release of cargo, ease of surface functionalization and complexation with other nanostructures. The application of CDs in overcoming drug resistance requires more investigation.

Nanobiotechnological approaches in osteosarcoma therapy: Versatile (nano)platforms for theranostic applications.

Constructive achievements in the field of nanobiotechnology and their translation into clinical course have led to increasing attention towards evaluation of their use for treatment of diseases, especially cancer. Osteosarcoma (OS) is one of the primary bone malignancies that affects both males and females in childhood and adolescence. Like other types of cancers, genetic and epigenetic mutations account for OS progression and several conventional therapies including chemotherapy and surgery are employed. However, survival rate of OS patients remains low and new therapies in this field are limited. The purpose of the current review is to provide a summary of nanostructures used in OS treatment. Drug and gene delivery by nanoplatforms have resulted in an accumulation of therapeutic agents for tumor cell suppression. Furthermore, co-delivery of genes and drugs by nanostructures are utilized in OS suppression to boost immunotherapy. Since tumor cells have distinct features such as acidic pH, stimuli-responsive nanoparticles have been developed to appropriately target OS. Besides, nanoplatforms can be used for biosensing and providing phototherapy to suppress OS. Furthermore, surface modification of nanoparticles with ligands can increase their specificity and selectivity towards OS cells. Clinical translation of current findings suggests that nanoplatforms have been effective in retarding tumor growth and improving survival of OS patients.

Dendrimers as nanoscale vectors: Unlocking the bars of cancer therapy.

Chemotherapy is the first choice in the treatment of cancer and is always preferred to other approaches such as radiation and surgery, but it has never met the need of patients for a safe and effective drug. Therefore, new advances in cancer treatment are now needed to reduce the side effects and burdens associated with chemotherapy for cancer patients. Targeted treatment using nanotechnology are now being actively explored as they could effectively deliver therapeutic agents to tumor cells without affecting normal cells. Dendrimers are promising nanocarriers with distinct physiochemical properties that have received considerable attention in cancer therapy studies, which is partly due to the numerous functional groups on their surface. In this review, we discuss the progress of different types of dendrimers as delivery systems in cancer therapy, focusing on the challenges, opportunities, and functionalities of the polymeric molecules. The paper also reviews the various role of dendrimers in their entry into cells via endocytosis, as well as the molecular and inflammatory pathways in cancer. In addition, various dendrimers-based drug delivery (e.g., pH-responsive, enzyme-responsive, redox-responsive, thermo-responsive, etc.) and lipid-, amino acid-, polymer- and nanoparticle-based modifications for gene delivery, as well as co-delivery of drugs and genes in cancer therapy with dendrimers, are presented. Finally, biosafety concerns and issues hindering the transition of dendrimers from research to the clinic are discussed to shed light on their clinical applications.

Advances in nanoparticle mediated targeting of RNA binding protein for cancer.

RNA binding proteins (RBPs) enact a very crucial part in the RNA directive processes. Atypical expression of these RBPs affects many steps of RNA metabolism, majorly altering its expression. Altered expression and dysfunction of RNA binding proteins lead to cancer progression and other diseases. We enumerate various available interventions, and recent findings focused on targeting RBPs for cancer therapy and diagnosis. The treatment, sensitization, chemoprevention, gene-mediated, and virus mediated interventions were studied to treat and diagnose cancer. The application of passively and actively targeted lipidic nanoparticles, polymeric nanoparticles, virus-based particles, and vaccine-based immunotherapy for the delivery of therapeutic agent/s against cancer are discussed. We also discuss the formulation aspect of nanoparticles for achieving delivery at the site of action and ongoing clinical trials targeting RBPs.

Synthesis and characterization of hybrid nanocarrier layered double hydroxide grafted by polyethylene glycol and gemcitabine.

For the past few years, organic-inorganic hybrid nanocarriers have been widely explored for effective drug delivery and preferable disease treatments. In this article, hydrothermal method was utilized to prepare fine dispersed layered double hydroxide (Mg-Al LDH) suspension. Polyethylene glycol (PEG) was grafted on the surface of LDH lamella in order to improve the dispersibility of LDH. Besides, the anti-cancer drug gemcitabine was grafted on the surface of LDH lamellas through chemical grafting. Hence a novel new type of organic-inorganic hybrid drug delivery system LDH-mPEG-Gemcitabine was obtained. In addition, the siRNA was intercalated into the LDH interlamination by ion exchange method to realize drug and gene co-delivery. The loading capacity of LDH and LDH-mPEG-Gemcitabine was evaluated by agarose gel electrophoresis. The characterization by laser particle size analyzer, TEM, FT-IR, XRD, in vitro cell viability and in vitro drug release demonstrated that LDH-mPEG-Gemcitabine possessed fine dispersibility, uniform morphology and particle size, fine biocompatibility, ideal drug loading and releasing capacity and held great potential to be used as a desired co-delivery system for drug and gene.

Ultrasound and Microbubbles for Targeted Drug Delivery to the Lung Endothelium in ARDS: Cellular Mechanisms and Therapeutic Opportunities.

Acute respiratory distress syndrome (ARDS) is characterized by increased permeability of the alveolar-capillary membrane, a thin barrier composed of adjacent monolayers of alveolar epithelial and lung microvascular endothelial cells. This results in pulmonary edema and severe hypoxemia and is a common cause of death after both viral (e.g., SARS-CoV-2) and bacterial pneumonia. The involvement of the lung in ARDS is notoriously heterogeneous, with consolidated and edematous lung abutting aerated, less injured regions. This makes treatment difficult, as most therapeutic approaches preferentially affect the normal lung regions or are distributed indiscriminately to other organs. In this review, we describe the use of thoracic ultrasound and microbubbles (USMB) to deliver therapeutic cargo (drugs, genes) preferentially to severely injured areas of the lung and in particular to the lung endothelium. While USMB has been explored in other organs, it has been under-appreciated in the treatment of lung injury since ultrasound energy is scattered by air. However, this limitation can be harnessed to direct therapy specifically to severely injured lungs. We explore the cellular mechanisms governing USMB and describe various permutations of cargo administration. Lastly, we discuss both the challenges and potential opportunities presented by USMB in the lung as a tool for both therapy and research.

PAMAM dendrimer as a talented multifunctional biomimetic nanocarrier for cancer diagnosis and therapy.

Poly(amidoamine) dendrimers (PAMAM) are novel polymeric highly branched architectures with well-defined nano-size, narrow polydispersity index and numerous active amine functional groups at the periphery. The highly attractive feature of modifiable multiple surface functionalities facilitates conjugation of various ligands for cancer targeting, imaging and therapy. As well as, solubilization, high drug encapsulation, inherent passive targeting ability will also contribute to the therapeutic success of dendrimers. Cancer researchers are very eager about the utility of PAMAM dendrimer as a drug carrier and non-viral gene vector. This review highlighted the potential of non-targeted and ligand targeted surface engineered PAMAM dendrimers for the delivery of anticancer drugs and gene therapeutics and briefly focus on the diagnostic imaging applications of PAMAM dendrimers.

Self-Assembling Derivative of Hydrocortisone as Glucocorticoid Receptor-Targeted Nanotherapeutics for Synergistic, Combination Therapy against Colorectal Tumor.

Hydrocortisone, a natural glucocorticoid secreted by adrenal and extra-adrenal tissues, locally governs the transcription of genes involved in inflammation, immune response, metabolism, and energy homeostasis via binding to its cognate glucocorticoid receptor (GR). In this study, we show that modified hydrocortisone (HC16), a cancer-selective cytotoxic molecule, showed synergism in combination with drugs like Doxorubicin and docetaxel, self-assembled into vesicles, entrapped docetaxel and complexed with anti-cancer plasmid DNA for enhanced killing of cancer cells. These vesicles exhibited GR-mediated nuclear localization, delivery of the p53 gene, and also inhibited cell viability selectively in RKO, HCT15, and CT26 colon cancer cells but not in normal cells like CHO and HEK293T. Apart from exerting its own anti-cancer activity, the self-assembled HC16 vesicles loaded with docetaxel sensitized the cancer cells to its drug cargo by downregulating the drug metabolizing CYP3A4 gene. This indirectly reduces the risk of nonspecific adverse effects in normal cells, as the viability of sensitized cancer cells could be significantly reduced even in low doses of cytotoxic docetaxel. The near infrared (NIR)-dye-associated self-assemblies accumulated in a colon tumor with higher orders of NIR intensity compared to those in a colon of healthy mice. Thereafter, the treatment of HC16-docetaxel-p53 vesicle/DNA complex led to significant tumor regression, which resulted in a cecum/body weight ratio in tumor-bearing mice similar to that of healthy mice measured at 24 h postcompletion of treatment. There was an up to 2.5-fold enhancement in the overall survivability of colon-tumor-bearing mice treated with HC16-docetaxel-p53 vesicle/DNA complexes when compared against the pristine docetaxel-treated groups. Further, the HC16-docetaxel-p53 vesicle/DNA complex-treated group showed reduced nuclear accumulation of cell proliferation marker Ki67, reduced protein levels of prosurvival and mesenchymal proteins like Bcl-2, PARP, vimentin, and N-cadherin, and increased the levels of pro-apoptotic activated caspases as compared to the pristine docetaxel-treated groups. The therapeutic package described herein is expected to find future use as a rational, multifaceted, GR-targeted approach for inhibiting colon tumor progression.

Recent Advances in the Use of Focused Ultrasound for Magnetic Resonance Image-Guided Therapeutic Nanoparticle Delivery to the Central Nervous System.

Targeting systemically-administered drugs and genes to specific regions of the central nervous system (CNS) remains a challenge. With applications extending into numerous disorders and cancers, there is an obvious need for approaches that facilitate the delivery of therapeutics across the impervious blood-brain barrier (BBB). Focused ultrasound (FUS) is an emerging treatment method that leverages acoustic energy to oscillate simultaneously administered contrast agent microbubbles. This FUS-mediated technique temporarily disrupts the BBB, allowing ordinarily impenetrable agents to diffuse and/or convect into the CNS. Under magnetic resonance image guidance, FUS and microbubbles enable regional targeting-limiting the large, and potentially toxic, dosage that is often characteristic of systemically-administered therapies. Subsequent to delivery across the BBB, therapeutics face yet another challenge: penetrating the electrostatically-charged, mesh-like brain parenchyma. Non-bioadhesive, encapsulated nanoparticles can help overcome this additional barrier to promote widespread treatment in selected target areas. Furthermore, nanoparticles offer significant advantages over conventional systemically-administered therapeutics. Surface modifications of nanoparticles can be engineered to enhance targeted cellular uptake, and nanoparticle formulations can be tailored to control many pharmacokinetic properties such as rate of drug liberation, distribution, and excretion. For instance, nanoparticles loaded with gene plasmids foster relatively stable transfection, thus obviating the need for multiple, successive treatments. As the formulations and applications of these nanoparticles can vary greatly, this review article provides an overview of FUS coupled with polymeric or lipid-based nanoparticles currently utilized for drug delivery, diagnosis, and assessment of function in the CNS.

Perspectives on Recent Progress in Focused Ultrasound Immunotherapy.

Immunotherapy holds tremendous promise as a strategy for eradicating solid tumors. However, poor T cell infiltration and persistence within most solid tumor microenvironments, as well as mechanisms of adaptive resistance, continue to severely limit the accessibility of most immunotherapies to a broad patient population. This limitation perpetuates the demand for allied therapeutic strategies. Among such strategies is focused ultrasound (FUS), a non-invasive, non-ionizing technique for precisely targeted acoustic energy deposition into tissues. FUS has gained remarkable attention over recent years as a modality for elicitation of immune mechanisms in cancer and other pathologies. In 2017, we published a comprehensive review paper detailing existing evidence for immune modulation and therapy with FUS, as well as impending challenges and opportunities of consideration for the field. Over the last two years, a multitude of clinical trials have come online to explore safety, feasibility, and efficacy of FUS for cancers of the brain and periphery - including the first clinical trial to combine FUS with immunotherapy. Moreover, the last two years have seen a surge in FUS immunotherapy presentations at therapeutic ultrasound scientific meetings. Given the burst of activity in this field, we submit that an update on FUS immunotherapy progress is timely. In this review, we offer an updated overview and perspectives on scientific and clinical development in the FUS immunotherapy domain.

Brief update on endocytosis of nanomedicines.

The complexity of nanoscale interactions between biomaterials and cells has limited the realization of the ultimate vision of nanotechnology in diagnostics and therapeutics. As such, significant effort has been devoted to advancing our understanding of the biophysical interactions of the myriad nanoparticles. Endocytosis of nanomedicine has drawn tremendous interest in the last decade. Here, we highlight the ever-present barriers to efficient intracellular delivery of nanoparticles as well as the current advances and strategies deployed to breach these barriers. We also introduce new barriers that have been largely overlooked such as the glycocalyx and macromolecular crowding. Additionally, we draw attention to the potential complications arising from the disruption of the newly discovered functions of the lysosomes. Novel strategies of exploiting the inherent intracellular defects in disease states to enhance delivery and the use of exosomes for bioanalytics and drug delivery are explored. Furthermore, we discuss the advances in imaging techniques like electron microscopy, super resolution fluorescence microscopy, and single particle tracking which have been instrumental in our growing understanding of intracellular pathways and nanoparticle trafficking. Finally, we advocate for the push towards more intravital analysis of nanoparticle transport phenomena using the multitude of techniques available to us. Unraveling the underlying mechanisms governing the cellular barriers to delivery and biological interactions of nanoparticles will guide the innovations capable of breaching these barriers.

Two dimensional carbon based nanocomposites as multimodal therapeutic and diagnostic platform: A biomedical and toxicological perspective.

Graphene based nanocomposites have revolutionized cancer treatment, diagnosis and imaging owing to its good compatibility, elegant flexibility, high surface area, low mass density along with excellent combined additive effect of graphene with other nanomaterials. This review inculcates the type of graphene based nanocomposites and their fabrication techniques to improve its properties as photothermal and theranostic platform. With decades' efforts, many significant breakthroughs in the method of synthesis and characterization in addition to various functionalization options of graphene based nanocomposite have paved a solid foundation for their potential applications in the cancer therapy. This work intends to provide a thorough, up-to-date holistic discussion on correlation of breakthroughs with their biomedical applications and illustrate how to utilize these breakthroughs to address long-standing challenges in the clinical translation of nanomedicines. This review also emphasizes on graphene based nanocomposites based toxicity concerns pertaining to delivery platforms.

Applications of Ultrasound to Stimulate Therapeutic Revascularization.

Many pathological conditions are characterized or caused by the presence of an insufficient or aberrant local vasculature. Thus, therapeutic approaches aimed at modulating the caliber and/or density of the vasculature by controlling angiogenesis and arteriogenesis have been under development for many years. As our understanding of the underlying cellular and molecular mechanisms of these vascular growth processes continues to grow, so too do the available targets for therapeutic intervention. Nonetheless, the tools needed to implement such therapies have often had inherent weaknesses (i.e., invasiveness, expense, poor targeting, and control) that preclude successful outcomes. Approximately 20 years ago, the potential for using ultrasound as a new tool for therapeutically manipulating angiogenesis and arteriogenesis began to emerge. Indeed, the ability of ultrasound, especially when used in combination with contrast agent microbubbles, to mechanically manipulate the microvasculature has opened several doors for exploration. In turn, multiple studies on the influence of ultrasound-mediated bioeffects on vascular growth and the use of ultrasound for the targeted stimulation of blood vessel growth via drug and gene delivery have been performed and published over the years. In this review article, we first discuss the basic principles of therapeutic ultrasound for stimulating angiogenesis and arteriogenesis. We then follow this with a comprehensive cataloging of studies that have used ultrasound for stimulating revascularization to date. Finally, we offer a brief perspective on the future of such approaches, in the context of both further research development and possible clinical translation.