Cell surface-nanoengineering for cancer targeting immunoregulation and precise immunotherapy.

Nanoparticles are the only materials small enough to target cells in the body, and therefore are crucial to targeted drug delivery. Issues with the synthesis, consistency, and bioactivity of these molecules are still being addressed, but base on current proof of concept studies there is a reason to believe that the 'holy grail' of targeted drug delivery might someday be achieved using nanoparticle-based systems.

Escalating medical expenses due to infectious diseases are causing huge socioeconomic pressure on mankind globally. The emergence of antibiotic resistance has further aggravated this problem. Drug-resistant pathogens are also capable of forming thick biofilms on biotic and abiotic surfaces to thrive in a harsh environment. To address these clinical problems, various strategies including antibacterial agent delivering matrices and bactericidal coatings strategies have been developed. In this review, we have discussed various types of polymeric vehicles such as hydrogels, sponges/cryogels, microgels, nanogels, and meshes, which are commonly used to deliver antibiotics, metal nanoparticles, and biocides. Compositions of these polymeric matrices have been elaborately depicted by elucidating their chemical interactions and potential activity have been discussed. On the other hand, various implant/device-surface coating strategies which exploit the release-active mechanism of bacterial killing are discussed in elaboration. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Implantable Materials and Surgical Technologies > Nanomaterials and Implants Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease.

Synthetic vectors for therapeutic nucleic acid delivery are currently competing significantly with their viral counter parts due to their reduced immunogenicity, large payload capacity, and ease of manufacture under GMP-compliant norms. The approval of Onpattro, a lipid-based siRNA therapeutic, and the proven clinical success of two lipid-based COVID-19 vaccines from Pfizer-BioNTech, and Moderna heralded the specific advantages of lipid-based systems among all other synthetic nucleic acid carriers. Lipid-based systems with diverse payloads-plasmid DNA (pDNA), antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), and messenger RNA (mRNA)-are now becoming a mature technology, with growing impact in the clinic. Research over four decades identified the key factors determining the therapeutic success of these multi-component systems. Here, we discuss the main nucleic acid-based technologies, presenting their mechanism of action, delivery barriers facing them, the structural properties of the payload as well as the component lipids that regulate physicochemical properties, pharmacokinetics and biodistribution, efficacy, and toxicity of the resultant nanoparticles. We further detail on the formulation parameters, evolution of the manufacturing techniques that generate reproducible and scalable outputs, and key manufacturing aspects that enable control over physicochemical properties of the resultant particles. Preclinical applications of some of these formulations that were successfully translated from in vitro studies to animal models are subsequently discussed. Finally, clinical success and failure of these systems starting from 1993 to present are highlighted, in a holistic literature review focused on lipid-based nucleic acid delivery systems. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

Photodynamic therapy (PDT) is a minimally invasive technique which has proven to be successful in the treatment of several types of tumors. This relatively simple method exploits three inseparable elements: phototoxic compound (photosensitizer [PS]), light source, and oxygen. Upon irradiation by light with specified wavelength, PS generates reactive oxygen species, which starts the cascade of reactions leading to cell death. The positive therapeutic outcome of PDT may be limited due to several aspects, including low water solubility of PSs, hampering their effective administration and blood circulation, as well as low tumor specificity, inefficient cellular uptake and activation energies requiring prolonged illumination times. One of the promising approaches to overcome these obstacles involves the use of carrier systems modulating pharmacokinetics and pharmacodynamics of the PSs. In the present review, we summarized current in vitro and in vivo studies regarding the use of nanoparticles as potential delivery devices for PSs to enhance their cellular uptake and cytotoxic properties, and thus-the therapeutic outcome of PDT. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Photodynamic therapy (PDT) has been used in the treatment of cancers and other benign diseases for several years in clinic. However, the hypoxia of tumors and the penetration limitation of excitation light to tissues can dramatically reduce the efficacy of PDT to cancers. To overcome these drawbacks, various assembled nanocarriers such as nanoparticles, nanocapsules, nanocrystals, and so on were introduced. The assembled nanocarriers have the ability of loading photosensitizers, delivering O2 into tumors, generating O2 in situ in tumors, as well as turning near-infrared (NIR) light, X-rays, and chemical energy into ultraviolet or visible light. Therefore, it is easy for the nanocarriers to improve the hypoxia microenvironment or increase the treatment depth of cancers, which will improve the efficiency of PDT to some degree. In recent years, a number of investigations were focused on these subjects. We will summarize the advances of nanocarriers in PDT, especially in O2 introduction PDT and deep PDT. The perspectives, challenges, and potential in translation of PDT will also be discussed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology-Inspired Nanomaterials > Lipid-Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Tumor microenvironment (TME) is generally featured by low pH values, high glutathione (GSH) concentrations, overproduced hydrogen peroxide (H2 O2 ), and severe hypoxia. These characteristics could provide an interior environment for origination and residence of tumor cells and would lead to tumor progression, metastasis, and drug resistance. Therefore, the development of TME-responsive smart nanosystems has shown significant potential to enhance the efficacy of current cancer treatments. Manganese dioxide (MnO2 )-based nanosystems have attracted growing attentions for applications in cancer treatment as an excellent TME-responsive theranostic platform, due to their tunable structures/morphologies, pH responsive degradation, and excellent catalytic activities. In this review, we mainly summarize the strategies of MnO2 and its nanocomposites to modulate TME, such as tumor hypoxia relief, excessive GSH depletion, glucose consumption, and tumor immunosuppressive microenvironment moderation. Such MnO2 -based TME modulation would be beneficial for a wide range of cancer therapies including photodynamic therapy, radiotherapy, sonodynamic therapy, chemodynamic therapy, starvation therapy, and immunotherapy. Next, some representative designs of MnO2 -based nanoplatforms in other tumor therapies are highlighted. Moreover, we will discuss the challenges and future perspectives of these MnO2 -based nanosystems for enhanced tumor treatment. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Alzheimer's disease (AD) is the most common cause of dementia, and there is currently no cure. The "β-amyloid cascade hypothesis" of AD is the basis of current understanding of AD pathogenesis and drug discovery. However, no AD models have fully validated this hypothesis. We recently developed a human stem cell culture model of AD by cultivating genetically modified human neural stem cells in a three-dimensional (3D) cell culture system. These cells were able to recapitulate key events of AD pathology including β-amyloid plaques and neurofibrillary tangles. In this review, we will discuss the progress and current limitations of AD mouse models and human stem cell models as well as explore the breakthroughs of 3D cell culture systems. We will also share our perspective on the potential of dish models of neurodegenerative diseases for studying pathogenic cascades and therapeutic drug discovery.

The emergence of the CRISPR/Cas9 system has ushered in a new era of genetic editing with vast implications for both therapeutic interventions and drug discovery. This essay explores the extent to which CRISPR/Cas9 elevates target efficiency and revolutionizes drug discovery. While this technology offers unprecedented efficiency, precision, and programmability in genome editing, concerns about off-target effects have arisen. The essay discusses the transformative impact of CRISPR/Cas9 in drug discovery, particularly in cancer research and combating antimicrobial resistance. It also highlights strategies for detecting and mitigating off-target effects, such as in silico prediction tools, experimental methods, and precision-enhancing techniques. Ultimately, CRISPR/Cas9’s potential is undeniable, but its full realization depends on ongoing research and refinement to optimize specificity and revolutionize the field of drug discovery.

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screening technology is redefining the landscape of drug discovery and therapeutic target identification by providing a precise and scalable platform for functional genomics. The development of extensive single-guide RNA (sgRNA) libraries enables high-throughput screening (HTS) that systematically investigates gene-drug interactions across the genome. This powerful approach has found broad applications in identifying drug targets for various diseases, including cancer, infectious diseases, metabolic disorders, and neurodegenerative conditions, playing a crucial role in elucidating drug mechanisms and facilitating drug screening. Despite challenges like off-target effects, data complexity, and ethical or regulatory concerns, ongoing advancements in CRISPR technology and bioinformatics are steadily overcoming these limitations. Additionally, by integrating with organoid models, artificial intelligence (AI), and big data technologies, CRISPR screening expands the scale, intelligence, and automation of drug discovery. This integration boosts data analysis efficiency and offers robust support for uncovering new therapeutic targets and mechanisms. This review outlines the fundamental principles and applications of CRISPR screening technology, delves into specific case studies and technical challenges, and highlights its expanding role in drug discovery and target identification. It also examines the potential for clinical translation and addresses the associated ethical and regulatory considerations.

Polymer conjugation can be considered one of the leading approaches within the vast field of nanotechnology-based drug delivery systems. In fact, such technology can be exploited for delivering an active molecule, such as a small drug, a protein, or genetic material, or it can be applied to other drug delivery systems as a strategy to improve their in vivo behavior or pharmacokinetic activities such as prolonging the half-life of a drug, conferring stealth properties, providing external stimuli responsiveness, and so on. If on the one hand, polymer conjugation with biotech drug is considered the linchpin of the protein delivery field boasting several products in clinical use, on the other, despite dedicated research, conjugation with low molecular weight drugs has not yet achieved the milestone of the first clinical approval. Some of the primary reasons for this debacle are the difficulties connected to achieving selective targeting to diseased tissue, organs, or cells, which is the main goal not only of polymer conjugation but of all delivery systems of small drugs. In light of the need to achieve better drug targeting, researchers are striving to identify more sophisticated, biocompatible delivery approaches and to open new horizons for drug targeting methodologies leading to successful clinical applications. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.

AI-powered therapeutic aptamer drug discovery: Targeting the CT-domain of CTGF for Duchenne muscular dystrophy

Structural biology plays a key role in therapeutic drug discovery by revealing mechanisms of drug leads against their macromolecular targets and allowing for the optimization of their structures to enhance their therapeutic properties. One way that structural biology has been widely performed is by crystallography, which encompasses protein expression, crystallization, diffraction data collection, and model building and refinement. While experiments employing these techniques often are hard for students to perform on their own, since they require steep expertise, equipment, and funding barriers, the crystallographic and adjacent experiences can offer students unique opportunities to learn valuable research skills that they can use for projects they may want to pursue in the future in an engaging, captivating manner.The Structural Nucleic Acid Anticancer Research Society (STARS) is a student-led nonprofit organization that aims to provide these educational opportunities in relatable and engaging ways to students by creating robust infrastructure needed to support K-8th educators, 9th-12th graders, and undergraduate students to implement inorganic crystal-growing and macromolecular crystallography club projects and outreach programs to provide valuable experiences and skills, such as micro pipetting solutions for experimental setups, analyzing molecular interactions in protein complexes, or practice diffracting crystals, to elevate students’ understanding and learning of crystal-growing and crystallography along with key scientific skills, such as observation, notetaking, and analysis skills, so that students may use these experiences for their own projects in the future.Our strategy is to provide club branch projects, which can have therapeutic significance, that (1) provide valuable scientific experiences to students; (2) are applicable to students’ research interests; (3) are thematically accessible and easily understandable in nature; and (4) are rendered much more feasible to perform through clear and concise handouts provided by STARS and through branch fundraising with clear budgets. In starting new STARS branches in K-12th and in undergraduate student populations, we aim to not only equip students with important scientific skills and experiences through club branch activities, such as crystal-growing or crystallography projects, and outreach programs, such as crystallography workshops and crystal-growing competitions, but also aim to build up student leaders in science by providing students the opportunity to advocate for their STARS branch mission and purpose, share their outreach and research message through presentations, and network with industry and academia leaders at, for example, the American Crystallographic Association conference.So far, STARS already has two STARS branches, where student leaders bring STARS programming and outreach to life. These two branches have together organized over 12 events and programs, such as crystal-growing competitions, crystallography workshops, and lecture series sessions over the past four years with 380+ participants cumulatively. However, to truly provide all students in the United States the crystal- growing and crystallography opportunities to learn valuable scientific skills and be inspired in research for the treatment of diseases, STARS aims to (1) fully streamline its club programming and outreach activities with clear guidance and handouts, which can enable our STARS programs to scale up; (2) foster inter-STARS branch communications and collaborations to form a network of research-focused students through our annual STARS meetings; (3) enable students more accessible opportunities to give presentations at the American Crystallographic Association (ACA) conference through the STARS Travel Grant; and (4) engage more K-12th and undergraduate students in not only inorganic crystal growing, but also protein crystallography through national crystallography competitions of proteins (such as with lysozyme, the chicken egg white protein).Crystallography is a unique research field that not only is very important for structural biology and therapeutic drug discovery research but also can easily captivate students with its beautiful inorganic and macromolecular crystals and structures. The Structural Nucleic Acid Anticancer Research Society (STARS) aims to capitalize on these inherent qualities to engage and empower students in crystal-growing, crystallography, and therapeutic research through our streamlined programs and club activities.

Arthritic injuries happen frequently during a lifetime due to accidents, sports, aging, diseases, etc. Such injuries can be cartilage/bone injuries, tendon injuries, ligament injuries, inflammation, pain, and/or synovitis. Oral and injective administration of therapeutics are typically used but cause many side effects. Transdermal administration is an alternative route for safe and efficient delivery. Transdermal formulations of non-steroidal anti-inflammatory drugs have been available on market for years and show promising efficacy in pain relieving, inflammation alleviation, infection control, and so on. Innovative transdermal patches, gels/films, and microneedles have also been widely explored as formulations to deliver therapeutics to combat arthritic injuries. However, transdermal formulations that halt disease progression and promote damage repair are translated slowly from lab bench to clinical applications. One major reason is that the skin barrier and synovial capsule barrier limit the efficacy of transdermal delivery. Recently, many nanocarriers, such as nanoparticles, nanolipids, nanoemulsions, nanocrystals, exosomes, etc., have been incorporated into transdermal formulations to advance drug delivery. The combined transdermal formulations show promising safety and efficacy. Therefore, this review will focus on stating the current development of nanomedicine-based transdermal formulations for the treatment of arthritic injuries. The advances, limitations, and future perspectives in this field will also be provided to inspire future studies and accelerate clinical translational studies. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Biology-Inspired Nanomaterials > Lipid-Based Structures.

Respiratory illnesses are prevalent around the world, and inhalation-based therapies provide an attractive, noninvasive means of directly delivering therapeutic agents to their site of action to improve treatment efficacy and limit adverse systemic side effects. Recent trends in medicine and nanoscience have prompted the development of inhalable nanomedicines to further enhance effectiveness, patient compliance, and quality of life for people suffering from lung cancer, chronic pulmonary diseases, and tuberculosis. Herein, we discuss recent advancements in the development of inhalable nanomaterial-based drug delivery systems and analyze several representative systems to illustrate their key design principles that can translate to improved therapeutic efficacy for prevalent respiratory diseases. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease.

With a growing health threat of bacterial resistance to antibiotics, the nanomaterials have been extensively studied as an alternative. It is assumed that antimicrobial nanomaterials can affect bacteria by several mechanisms simultaneously and thereby overcome antibiotic resistance. Another promising potential use is employing nanomaterials as nanocarriers for antibiotics in order to overcome bacterial defense mechanisms. The passive targeting of nanomaterials is the often used strategy for bacterial treatment, including intracellular infections of macrophages. Furthermore, the specific targeting enhances the efficacy of antimicrobials and reduces side effects. This review aims to discuss advantages, disadvantages, and challenges of nanomaterials in the context of the targeting strategies for antimicrobials as advanced tools for treatments of bacterial infections. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease.