Advanced drug delivery reviews最新文献

CRISPR/Cas technology presents a promising approach for treating a wide range of diseases, including cancer and genetic disorders. Despite its potential, the translation of CRISPR/Cas into effective in-vivo gene therapy encounters challenges, primarily due to the need for safe and efficient delivery mechanisms. Lipid nanoparticles (LNPs), FDA-approved for RNA delivery, show potential for delivering also CRISPR/Cas, offering the capability to efficiently encapsulate large mRNA molecules with single guide RNAs. However, achieving precise targeting in-vivo remains a significant obstacle, necessitating further research into optimizing LNP formulations. Strategies to enhance specificity, such as modifying LNP structures and incorporating targeting ligands, are explored to improve organ and cell type targeting. Furthermore, the development of base and prime editing technology presents a potential breakthrough, offering precise modifications without generating double-strand breaks (DSBs). Prime editing, particularly when delivered via targeted LNPs, holds promise for treating diverse diseases safely and precisely. This review assesses both the progress made and the persistent challenges faced in using LNP-encapsulated CRISPR-based technologies for therapeutic purposes, with a particular focus on clinical translation.

Gene editing technologies have the potential to correct genetic disorders by modifying, inserting, or deleting specific DNA sequences or genes, paving the way for a new class of genetic therapies. While gene editing tools continue to be improved to increase their precision and efficiency, the limited efficacy of in vivo delivery remains a major hurdle for clinical use. An ideal delivery vehicle should be able to target a sufficient number of diseased cells in a transient time window to maximize on-target editing and mitigate off-target events and immunogenicity.

Here, we review major advances in novel delivery platforms based on cell-derived vesicles − extracellular vesicles and virus-like particles − for transient delivery of gene editing payloads. We discuss major findings regarding packaging, in vivo biodistribution, therapeutic efficacy, and safety concerns of cell-derived vesicles delivery of gene editing cargos and their potential for clinical translation.

Administered drug molecules, whether dissolved or solubilized, have the potential to precipitate and accumulate as solid forms in tissues and cells within the body. This phase transition can significantly impact the pharmacokinetics of treatment. It is thus crucial to gain an understanding of how drug solubility/permeability, drug formulations and routes of administration affect in vivo behaviors of drug deposition. This review examines literature reports on the drug deposition in tissues and cells of poorly water-soluble drugs, as well as underlying physical mechanisms that lead to precipitation. Our work particularly highlights drug deposition in macrophages and the subcellular fate of precipitated drugs. We also propose a tissue permeability-based classification framework to evaluate precipitation potentials of poorly soluble drugs in major organs and tissues. The impact on pharmacokinetics is further discussed and needs to be considered in developing drug delivery systems. Finally, bioimaging techniques that are used to examine aggregated states and the intracellular trafficking of absorbed drugs are summarized.

Mitochondrial genome (mtDNA) independent of nuclear gene is a set of double-stranded circular DNA that encodes 13 proteins, 2 ribosomal RNAs and 22 mitochondrial transfer RNAs, all of which play vital roles in functions as well as behaviors of mitochondria. Mutations in mtDNA result in various mitochondrial disorders without available cures. However, the manipulation of mtDNA via the mitochondria-targeted gene delivery faces formidable barriers, particularly owing to the mitochondrial double membrane. Given the fact that there are various transport channels on the mitochondrial membrane used to transfer a variety of endogenous substances to maintain the normal functions of mitochondria, mitochondrial endogenous substance transport-inspired nanomaterials have been proposed for mitochondria-targeted gene delivery. In this review, we summarize mitochondria-targeted gene delivery systems based on different mitochondrial endogenous substance transport pathways. These are categorized into mitochondrial steroid hormones import pathways-inspired nanomaterials, protein import pathways-inspired nanomaterials and other mitochondria-targeted gene delivery nanomaterials. We also review the applications and challenges involved in current mitochondrial gene editing systems. This review delves into the approaches of mitochondria-targeted gene delivery, providing details on the design of mitochondria-targeted delivery systems and the limitations regarding the various technologies. Despite the progress in this field is currently slow, the ongoing exploration of mitochondrial endogenous substance transport and mitochondrial biological phenomena may act as a crucial breakthrough in the targeted delivery of gene into mitochondria and even the manipulation of mtDNA.

Extracellular Matrix (ECM) scaffolds and biomaterials have been widely used for decades across a variety of diverse clinical applications and have been implanted in millions of patients worldwide. ECM-based biomaterials have been especially successful in soft tissue repair applications but their utility in other clinical applications such as for regeneration of bone or neural tissue is less well understood. The beneficial healing outcome with the use of ECM biomaterials is the result of their biocompatibility, their biophysical properties and their ability to modify cell behavior after injury. As a consequence of successful clinical outcomes, there has been motivation for the development of next-generation formulations of ECM materials ranging from hydrogels, bioinks, powders, to whole organ or tissue scaffolds. The continued development of novel ECM formulations as well as active research interest in these materials ensures a wealth of possibilities for future clinical translation and innovation in regenerative medicine. The clinical translation of next generation formulations ECM scaffolds faces predictable challenges such as manufacturing, manageable regulatory pathways, surgical implantation, and the cost required to address these challenges. The current status of ECM-based biomaterials, including clinical translation, novel formulations and therapies currently under development, and the challenges that limit clinical translation of ECM biomaterials are reviewed herein.

Emerging evidence reveal that tumor-associated bacteria (TAB) can facilitate the initiation and progression of multiple types of cancer. Recent work has emphasized the significant role of intestinal microbiota, particularly bacteria, plays in affecting responses to chemo- and immuno-therapies. Hence, it seems feasible to improve cancer treatment outcomes by targeting intestinal bacteria. While considering variable richness of the intestinal microbiota and diverse components among individuals, direct manipulating the gut microbiota is complicated in clinic. Tumor initiation and progression requires the gut microbiota-derived metabolites to contact and reprogram neoplastic cells. Hence, directly targeting tumor-associated bacteria metabolites may have the potential to provide alternative and innovative strategies to bypass the gut microbiota for cancer therapy. As such, there are great opportunities to explore holistic approaches that incorporates TAB-derived metabolites and related metabolic signals modulation for cancer therapy. In this review, we will focus on key opportunistic areas by targeting TAB-derived metabolites and related metabolic signals, but not bacteria itself, for cancer treatment, and elucidate future challenges that need to be addressed in this emerging field.

Brain organoids hold great potential for modeling human brain development and pathogenesis. They recapitulate certain aspects of the transcriptional trajectory, cellular diversity, tissue architecture and functions of the developing brain. In this review, we explore the engineering strategies to control the molecular-, cellular- and tissue-level inputs to achieve high-fidelity brain organoids. We review the application of brain organoids in neural disorder modeling and emerging bioengineering methods to improve data collection and feature extraction at multiscale. The integration of multiscale engineering strategies and analytical methods has significant potential to advance insight into neurological disorders and accelerate drug development.

Nucleic acid technology has revolutionized vaccine development, enabling rapid design and production of RNA and DNA vaccines for prevention and treatment of diseases. The successful deployment of mRNA and plasmid DNA vaccines against COVID-19 has further validated the technology. At present, mRNA platform is prevailing due to its higher efficacy, while DNA platform is undergoing rapid evolution because it possesses unique advantages that can potentially overcome the problems associated with the mRNA platform. To help understand the recent performances of the two vaccine platforms and recognize their clinical potentials in the future, this review compares the advantages and drawbacks of mRNA and DNA vaccines that are currently known in the literature, in terms of development timeline, financial cost, ease of distribution, efficacy, safety, and regulatory approval of products. Additionally, the review discusses the ongoing clinical trials, strategies for improvement, and alternative designs of RNA and DNA platforms for vaccination.

Chronic non-healing wounds persist as a substantial burden for healthcare systems, influenced by factors such as aging, diabetes, and obesity. In contrast to the traditionally pro-regenerative emphasis of therapies, the recognition of the immune system integral role in wound healing has significantly grown, instigating an approach shift towards immunological processes. Thus, this review explores the wound healing process, highlighting the engagement of the immune system, and delving into the behaviors of innate and adaptive immune cells in chronic wound scenarios. Moreover, the article investigates biomaterial-based strategies for the modulation of the immune system, elucidating how the adjustment of their physicochemical properties or their synergistic combination with other agents such as drugs, proteins or mesenchymal stromal cells can effectively modulate the behaviors of different immune cells. Finally this review explores various strategies based on synthetic and biological nanostructures, including extracellular vesicles, to finely tune the immune system as natural immunomodulators or therapeutic nanocarriers with promising biophysical properties.

Microneedles (MNs) offer minimally-invasive access to interstitial fluid (ISF) — a potent alternative to blood in terms of monitoring physiological analytes. This property is particularly advantageous for the painless detection and monitoring of drugs and biomolecules. However, the complexity of the skin environment, coupled with the inherent nature of the analytes being detected and the inherent physical properties of MNs, pose challenges when conducting physiological monitoring using this fluid. In this review, we discuss different sensing mechanisms and highlight advancements in monitoring different targets, with a particular focus on drug monitoring. We further list the current challenges facing the field and conclude by discussing aspects of MN design which serve to enhance their performance when monitoring different classes of analytes.