Biological Drug Delivery Research Articles

Mitophagy and its regulatory mechanisms in the biological effects of nanomaterials.

Mitophagy is a selective cellular process critical for the removal of damaged mitochondria. It is essential in regulating mitochondrial number, ensuring mitochondrial functionality, and maintaining cellular equilibrium, ultimately influencing cell destiny. Numerous pathologies, such as neurodegenerative diseases, cardiovascular disorders, cancers, and various other conditions, are associated with mitochondrial dysfunctions. Thus, a detailed exploration of the regulatory mechanisms of mitophagy is pivotal for enhancing our understanding and for the discovery of novel preventive and therapeutic options for these diseases. Nanomaterials have become integral in biomedicine and various other sectors, offering advanced solutions for medical uses including biological imaging, drug delivery, and disease diagnostics and therapy. Mitophagy is vital in managing the cellular effects elicited by nanomaterials. This review provides a comprehensive analysis of the molecular mechanisms underpinning mitophagy, underscoring its significant influence on the biological responses of cells to nanomaterials. Nanoparticles can initiate mitophagy via various pathways, among which the PINK1-Parkin pathway is critical for cellular defense against nanomaterial-induced damage by promoting mitophagy. The role of mitophagy in biological effects was induced by nanomaterials, which are associated with alterations in Ca2+ levels, the production of reactive oxygen species, endoplasmic reticulum stress, and lysosomal damage.

Engineered self-regulating macrophages for targeted anti-inflammatory drug delivery

BackgroundRheumatoid arthritis (RA) is a systemic autoimmune disease characterized by increased levels of inflammation that primarily manifests in the joints. Macrophages act as key drivers for the progression of RA, contributing to the perpetuation of chronic inflammation and dysregulation of pro-inflammatory cytokines such as interleukin 1 (IL-1). The goal of this study was to develop a macrophage-based cell therapy for biologic drug delivery in an autoregulated manner.MethodsFor proof-of-concept, we developed “smart” macrophages to mitigate the effects of IL-1 by delivering its inhibitor, IL-1 receptor antagonist (IL-1Ra). Bone marrow-derived macrophages were lentivirally transduced with a synthetic gene circuit that uses an NF-κB inducible promoter upstream of either the Il1rn or firefly luciferase transgenes. Two types of joint like cells were utilized to examine therapeutic protection in vitro, miPSCs derived cartilage and isolated primary mouse synovial fibroblasts while the K/BxN mouse model of RA was utilized to examine in vivo therapeutic protection.ResultsThese engineered macrophages were able to repeatably produce therapeutic levels of IL-1Ra that could successfully mitigate inflammatory activation in co-culture with both tissue-engineered cartilage constructs and synovial fibroblasts. Following injection in vivo, macrophages homed to sites of inflammation and mitigated disease severity in the K/BxN mouse model of RA.ConclusionThese findings demonstrate the successful development of engineered macrophages that possess the ability for controlled, autoregulated production of IL-1 based on inflammatory signaling such as via the NF-κB pathway to mitigate the effects of this cytokine for applications in RA or other inflammatory diseases. This system provides proof of concept for applications in other immune cell types as self-regulating delivery systems for therapeutic applications in a range of diseases.

The Astonishing Accomplishment of Biological Drug Delivery using Lipid Nanoparticles: An Ubiquitous Review.

Biotech drugs, including proteins, hormones, enzymes, DNA/RNA therapies, and cell-based treatments, are gaining popularity due to their effectiveness. However, effective delivery systems are needed to overcome administration challenges. Lipid nanoparticles (LNPs) have emerged as promising carriers for various therapies. LNPs are biocompatible, less likely to cause adverse reactions, and can stabilize delicate biological drugs, enhancing their stability and solubility. Scalable and cost-effective manufacturing processes make LNPs suitable for largescale production. Despite recent research efforts, challenges in stability, toxicity, and regulatory concerns have limited the commercial availability of LNP-based products. This review explores the applications, administration routes, challenges, and future directions of LNPs in delivering biopharmaceuticals.

Preparation of Gradient HEA-DAC/HPA Hydrogels by Limited Domain Swelling Method.

Hydrogels are widely used in biological dressing, tissue scaffolding, drug delivery, sensors, and other promising applications owing to their water-rich soft structures, biocompatibility, and adjustable mechanical properties. However, most of the conventional hydrogels are isotropic. The anisotropic structures existed widely in the organizational structure of plants and animals, which played a crucial role in biological systems. In this work, a method of limited domain swelling to prepare anisotropic hydrogels is proposed. Through spatially controlled swelling, the extension direction of hydrogels can be limited by a tailored mold, further achieving anisotropic hydrogels with concentration gradients. The external solution serves as a swelling solution to promote swelling and extension of the hydrogel matrix in a mold which can control the extension direction. Due to the diversity of external solutions, the method can be applied to prepare a variety of stimulus-responsive polymers. The limited domain swelling method is promising for the construction of anisotropic hydrogels with different structures and properties.

Nanomedicines with Versatile GSH-Responsive Linkers for Cancer Theranostics.

Glutathione (GSH)-responsive nanomedicines have generated significant interest in biochemistry, oncology, and material sciences due to their diverse applications, including chemical and biological sensors, diagnostics, and drug delivery systems. The effectiveness of these smart GSH-responsive nanomedicines depends critically on the choice of GSH-responsive linkers. Despite their crucial role, comprehensive reviews of GSH-responsive linkers are scarce, revealing a gap in the current literature. This review addresses this gap by systematically summarizing various GSH-responsive linkers and exploring their potential applications in cancer treatment. We provide an overview of the mechanisms of action of these linkers and their bioapplications, evaluating their advantages and limitations. The insights presented aim to guide the development of advanced GSH-responsive agents for cancer diagnosis and therapy.

Advancements in oral insulin: A century of research and the emergence of targeted nanoparticle strategies

AbstractWith the growing prevalence of diabetes, there is an urgent demand for a user‐friendly treatment option that minimizes side effects related to the use of subcutaneous injections. Scientists have dedicated over a century to developing an oral dosage form of insulin that can be administrated orally. The oral route of administration is the most desirable route for regularly dosed drugs in terms of safety and patient compliance. However, oral delivery of insulin remains a formidable challenge due to its intrinsically limited ability to cross the intestinal epithelium membrane and susceptibility to enzymatic degradation. This article reviews oral insulin research over the past decade, with a particular focus on surface modifications of nanoparticles (NPs). Various strategies involving controlling surface charges, utilizing protective proteins, and targeting specific receptors with ligands have been explored. Notably, surface modifications of the NPs for targeting specific intestinal receptors have shown promise in enhancing insulin oral absorption and bioavailability. Advanced technologies such as oral microneedles and gene therapy have also been developed, but their safety requires further assessment. Despite encouraging preclinical results across numerous strategies, the current clinical evidence is less optimistic. In summary, the present findings highlight the substantial journey that still lies ahead before achieving successful oral delivery of insulin.Practical Applications: This review provides a summary of recent progress in oral insulin delivery, particularly highlighting surface‐modified functional nanoparticles serving as an effective drug delivery system, which offers valuable information to the researchers. Due to the limited effectiveness of oral protein drugs caused by biological barriers, innovative technologies and drug delivery systems have been developed to overcome these obstacles and achieve therapeutic goals. This review concluded that surface modifications to nanoparticles can improve insulin stability and permeability, thereby enhancing oral bioavailability. It could assist researchers in developing more effective and patient‐friendly oral drug delivery systems.

Engineered Self-Regulating Macrophages for Targeted Anti-inflammatory Drug Delivery.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by increased levels of inflammation that primarily manifests in the joints. Macrophages act as key drivers for the progression of RA, contributing to the perpetuation of chronic inflammation and dysregulation of pro-inflammatory cytokines such as interleukin 1 (IL-1). The goal of this study was to develop a macrophage-based cell therapy for biologic drug delivery in an autoregulated manner. For proof-of-concept, we developed "smart" macrophages to mitigate the effects of IL-1 by delivering its inhibitor, IL-1 receptor antagonist (IL-1Ra). Bone marrow-derived macrophages were lentivirally transduced with a synthetic gene circuit that uses an NF-κB inducible promoter upstream of either the Il1rn or firefly luciferase transgenes. Two types of joint like cells were utilized to examine therapeutic protection in vitro, miPSCs derived cartilage and isolated primary mouse synovial fibroblasts while the K/BxN mouse model of RA was utilized to examine in vivo therapeutic protection. These engineered macrophages were able to repeatably produce therapeutic levels of IL-1Ra that could successfully mitigate inflammatory activation in co-culture with both tissue engineered cartilage constructs and synovial fibroblasts. Following injection in vivo, macrophages homed to sites of inflammation and mitigated disease severity in the K/BxN mouse model of RA. These findings demonstrate the successful development of engineered macrophages that possess the ability for controlled, autoregulated production of IL-1 based on inflammatory signaling such as the NF-κB pathway to mitigate the effects of this cytokine for applications in RA or other inflammatory diseases. This system provides proof of concept for applications in other immune cell types as self-regulating delivery systems for therapeutic applications in a range of diseases.

Bisphosphonates activated keratin assembled nanoparticle targeting bone fracture for enhanced immunomodulatory and osteoinductivity

Bone fractures pose significant clinical challenges and require innovative solutions for effective treatment and rapid recovery. Nanoscale protein-based materials are prominent in biotechnology and biomedicine, demonstrating versatility in biological processes and drug delivery. Herein, we designed and fabricated self-assembled keratin nanoparticles via a bisphosphonate (BP)-activated conformation-conservative assembly process. We determined the structural properties of the nanoparticles and explored the immunomodulatory and osteoinductivity functions retained from keratin. In addition, the keratin-BP nanoparticles could repair bone fractures. This study on multifunctional self-assembled protein-drug nanoparticles provides useful baseline data for exploring novel therapeutic options for acute bone fracture and other diseases.

Green synthesis of gold nanoparticles obtained from Punica granatum flower extract for phytochemical determination and antibacterial activity

Numerous biomedical applications such as biological detection, drug delivery, diagnostic imaging and tissue engineering, have incorporated nanotechnology. Parts of the pomegranate (Punica granatum) flower are known to have strong antibacterial properties. In this study, the anti-susceptibility test was used to look into the green synthesis of gold nanoparticles using Punica granatum and the inhibitory effect of these particles. According to the current study, prepared AuNPs were evaluated using a variety of methods including UV-visible spectrophotometry, FTIR, SEM and GC-MS to identify the phytochemicals. The bacterial and fungal species Candida albicans and Malassezia furfur that are inhibited by the synthetic colloidal gold nanoparticles made with Punica granatum flower extract include Escherichia coli, Pseudomonas, Staphylococcus, Klebsiella pneumoniae and Protea. In this work, we describe a simple, quick and reproducible method for the environmentally friendly synthesis of AuNPs without the need for expensive reducing agents. Simple incubation of a flower extract with aqueous gold ions at ambient temperature resulted in ‘medium monodisperse’ nanoparticles, suggesting that the plant extract acted as a strong reducing agent.

Carbon Nanodots Inhibit Tumor Necrosis Factor-α-Induced Endothelial Inflammation through Scavenging Hydrogen Peroxide and Upregulating Antioxidant Gene Expression in EA.hy926 Endothelial Cells.

Carbon nanodots (CNDs) are a new type of nanomaterial with a size of less than 10 nanometers and excellent biocompatibility, widely used in fields such as biological imaging, transmission, diagnosis, and drug delivery. However, its potential and mechanism to mediate endothelial inflammation have yet to be explored. Here, we report that the uptake of CNDs by EA.hy926 endothelial cells is both time and dose dependent. The concentration of CNDs used in this experiment was found to not affect cell viability. TNF-α is a known biomarker of vascular inflammation. Cells treated with CNDs for 24 h significantly inhibited TNF-α (0.5 ng/mL)-induced expression of intracellular adhesion molecule 1 (ICAM-1) and interleukin 8 (IL-8). ICAM-1 and IL-8 are two key molecules responsible for the activation and the firm adhesion of monocytes to activated endothelial cells for the initiation of atherosclerosis. ROS, such as hydrogen peroxide, play an important role in TNF-α-induced inflammation. Interestingly, we found that CNDs effectively scavenged H2O2 in a dose-dependent manner. CNDs treatment also increased the activity of the antioxidant enzyme NQO1 in EA.hy926 endothelial cells indicating the antioxidant properties of CNDs. These results suggest that the anti-inflammatory effects of CNDs may be due to the direct H2O2 scavenging properties of CNDs and the indirect upregulation of antioxidant enzyme NQO1 activity in endothelial cells. In conclusion, CND can inhibit TNF-α-induced endothelial inflammation, possibly due to its direct scavenging of H2O2 and the indirect upregulation of antioxidant enzyme NQO1 activity in endothelial cells.

Lysophosphatidic acid responsive photosensitive supramolecular organic frameworks for tumor imaging, drug loading, and photodynamic therapy

Supramolecular organic frameworks have been widely applied for biological detection and drug delivery. In this study, a supramolecular organic framework (SOF) is constructed through the self-assembly of a highly photosensitive triarylphosphine oxide guest molecule, OTPP-6-Methyl, with cucurbit [8] uril (CB [8]). The formation of the SOF gradually enhances the weak fluorescence of OTPP-6-Methyl owing to the restriction of the molecular folding motion. Although the high positive charge of OTPP-6-Methyl facilitates binding to various negatively charged substances, the SOF system only demonstrated an obvious fluorescence response to LPA, a biomarker of ovarian cancer, via the disassembly of SOF and subsequent binding of OTPP-6-Methyl with LPA. The fluorescence changes during the entire process are insufficient to allow the sensitive detection of LPA; thus, we further designed a FRET system by introducing Cy5, which can act as an energy receptor to achieve a ratiometric readout for LPA. The tumor-targeting cRGD group was introduced into the SOF system as part of another guest molecule, OTPP-5-M−1−cRGD, to improve the tumor-targeting ability of the SOF system. The SOF system further improves the photosensitivity of guest molecules, and is therefore used in the in vivo imaging of ovarian cancer subcutaneous tumors and as a DDS for loading DOX for the combined in vivo chemotherapy and photodynamic treatment of tumors.

Genetically engineered macrophages derived from iPSCs for self-regulating delivery of anti-inflammatory biologic drugs.

In rheumatoid arthritis, dysregulated cytokine signaling has been implicated as a primary factor in chronic inflammation. Many antirheumatic and biological therapies are used to suppress joint inflammation, but despite these advances, effectiveness is not universal, and delivery is often at high doses, which can predispose patients to significant off-target effects. During chronic inflammation, the inappropriate regulation of signaling factors by macrophages accelerates progression of disease by driving an imbalance of inflammatory cytokines, making macrophages an ideal cellular target. To develop a macrophage-based therapy to treat chronic inflammation, we engineered a novel induced pluripotent stem cell (iPSC)-derived macrophage capable of delivering soluble TNF receptor 1 (TNFR1), an anti-inflammatory biologic inhibitor of tumor necrosis factor alpha (TNF-α), in an auto-regulated manner in response to TNF-α. Murine iPSCs were differentiated into macrophages (iMACs) over a 17-day optimized protocol with continued successful differentiation confirmed at key timepoints. Varying inflammatory and immunomodulatory stimuli demonstrated traditional macrophage function and phenotypes. In response to TNF-α, therapeutic iMACs produced high levels of sTNFR1 in an autoregulated manner, which inhibited inflammatory signaling. This self-regulating iMAC system demonstrated the potential for macrophage-based drug delivery as a novel therapeutic approach for a variety of chronic inflammatory diseases.

Pain-free oral delivery of biologic drugs using intestinal peristalsis-actuated microneedle robots.

Biologic drugs hold immense promise for medical treatments, but their oral delivery remains a daunting challenge due to the harsh digestive environment and restricted gastrointestinal absorption. Here, inspired by the porcupinefish's ability to inflate itself and deploy its spines for defense, we proposed an intestinal microneedle robot designed to absorb intestinal fluids for rapid inflation and inject drug-loaded microneedles into the insensate intestinal wall for drug delivery. Upon reaching the equilibrium volume, the microneedle robot leverages rhythmic peristaltic contraction for mucosa penetration. The robot's barbed microneedles can then detach from its body during peristaltic relaxation and retain in the mucosa for drug releasing. Extensive in vivo experiments involving 14 minipigs confirmed the effectiveness of the intestinal peristalsis for microrobot actuation and demonstrated comparable insulin delivery efficacy to subcutaneous injection. The ingestible peristalsis-actuated microneedle robots may transform the oral administration of biologic drugs that primary relies on parenteral injection currently.

Chemical and Structural Engineering of Gelatin-Based Delivery Systems for Therapeutic Applications: A Review.

As a biodegradable and biocompatible protein derived from collagen, gelatin has been extensively exploited as a fundamental component of biological scaffolds and drug delivery systems for precise medicine. The easily engineered gelatin holds great promise in formulating various delivery systems to protect and enhance the efficacy of drugs for improving the safety and effectiveness of numerous pharmaceuticals. The remarkable biocompatibility and adjustable mechanical properties of gelatin permit the construction of active 3D scaffolds to accelerate the regeneration of injured tissues and organs. In this Review, we delve into diverse strategies for fabricating and functionalizing gelatin-based structures, which are applicable to gene and drug delivery as well as tissue engineering. We emphasized the advantages of various gelatin derivatives, including methacryloyl gelatin, polyethylene glycol-modified gelatin, thiolated gelatin, and alendronate-modified gelatin. These derivatives exhibit excellent physicochemical and biological properties, allowing the fabrication of tailor-made structures for biomedical applications. Additionally, we explored the latest developments in the modulation of their physicochemical properties by combining additive materials and manufacturing platforms, outlining the design of multifunctional gelatin-based micro-, nano-, and macrostructures. While discussing the current limitations, we also addressed the challenges that need to be overcome for clinical translation, including high manufacturing costs, limited application scenarios, and potential immunogenicity. This Review provides insight into how the structural and chemical engineering of gelatin can be leveraged to pave the way for significant advancements in biomedical applications and the improvement of patient outcomes.

CB[8]- and triarylboron-based supramolecular organic framework for microRNA detection, tumor-targeted drug delivery, and photodynamic therapy.

Supramolecular organic frameworks (SOFs) are widely used for biological detection and drug delivery. In this study, a SOF system was fabricated through the self-assembly of photosensitive triarylboron (TAB), TAB-6-methyl, and CB[8]. The maximum fluorescence emission of TAB-6-methyl was greatly enhanced and red-shifted from 560 nm to 610 nm after SOF formation. The SOF can specifically respond to a microRNA by dissembling and then combining with microRNA, which is accompanied by a fluorescence shift from 610 nm to 560 nm, thus providing a ratiometric readout for microRNA detection. The photosensitivity of TAB-6-methyl can be further improved by forming a SOF, which can be used in photodynamic therapy. By constructing another guest molecule, TAB-5-1-cRGD, we successfully embedded cRGD in the SOF system to improve its tumor-targeting ability. Moreover, we used this SOF system as a fluorescence imaging probe for targeted tumor imaging and as a drug carrier system for loading DOX to achieve combined photodynamic and chemotherapy treatment of tumors.

Therapeutic Management of Malignant Wounds: An Update.

Malignant fungating wounds (MFW) are severe skin conditions generating tremendous distress in oncological patients with advanced cancer stages because of pain, malodor, exudation, pruritus, inflammation, edema, and bleeding. The classical therapeutic approaches such as surgery, opioids, antimicrobials, and application of different wound dressings are failing in handling pain, odor, and infection control, thus urgently requiring the development of alternative strategies. The aim of this review was to provide an update on the current therapeutic strategies and the perspectives on developing novel alternatives for better malignant wound management. The last decade screened literature evidenced an increasing interest in developing natural treatment alternatives based on beehive, plant extracts, pure vegetal compounds, and bacteriocins. Promising therapeutics can also be envisaged by involving nanotechnology due to either intrinsic biological activities or drug delivery properties of nanomaterials. Despite recent progress in the field of malignant wound care, the literature is still mainly based on in vitro and in vivo studies on small animal models, while the case reports and clinical trials (less than 10 and only one providing public results) remain scarce. Some innovative treatment approaches are used in clinical practice without prior extensive testing in fungating wound patients. Extensive research is urgently needed to fill this knowledge gap and translate the identified promising therapeutic approaches to more advanced testing stages toward creating multidimensional wound care strategies.

Functional structures assembled based on Au clusters with practical applications.

The advancement of gold nanoclusters (Au NCs) has given rise to a new era in fabricating functional materials due to their controllable morphology, stable optical properties, and excellent biocompatibility. Assemblies based on Au NCs demonstrate significant potentiality in constructing multiple structures as acceptable agents in applications such as sensing, imaging technology, and drug delivery systems. In addition, the assembled strategies illustrate the integration mechanism between each component while facing material requirement. It is necessary to provide supplementary and comprehensive reviews on the assembled functional structures (based Au NCs), which hold promise for applications and could expand their functional range and potential applications. This review focuses on the assembled structures of Au NCs in combination with metals, metal oxides, and non-metal materials, which are intricately arranged through various interaction forces including covalent bonds and metal coordination, resulting in a diverse array of multifunctional Au NC assemblies. These assemblies have widespread applications in fields such as biological imaging, drug delivery, and optical devices. The review concludes by highlighting the challenges and future prospects of Au NC assemblies, emphasizing the importance of continued research to advance nanomaterial assembly innovation.

Advancements and Challenges in the Application of Metal-Organic Framework (MOF) Nanocomposites for Tumor Diagnosis and Treatment.

Nanoscale metal-organic frameworks (MOFs) offer high biocompatibility, nanomaterial permeability, substantial specific surface area, and well-defined pores. These properties make MOFs valuable in biomedical applications, including biological targeting and drug delivery. They also play a critical role in tumor diagnosis and treatment, including tumor cell targeting, identification, imaging, and therapeutic methods such as drug delivery, photothermal effects, photodynamic therapy, and immunogenic cell death. The diversity of MOFs with different metal centers, organics, and surface modifications underscores their multifaceted contributions to tumor research and treatment. This review is a summary of these roles and mechanisms. The final section of this review summarizes the current state of the field and discusses prospects that may bring MOFs closer to pharmaceutical applications.

Plant‐Derived Nanomaterials for Targeted Biological Applications and Smart Agriculture

AbstractBiologically inspired nanomaterials and nanotechnology have advanced in almost all scientific and technological research areas, including biomedical applications and agriculture. Nanomaterials hold immense potential for applications in biomedical and agricultural applications. By harnessing the natural capabilities of plants as sources of reducing and capping agents, the synthesis of nanomaterials becomes cost‐effective eco‐friendly, and yields biocompatible products. Here, we provide a comprehensive overview of various plant‐derived nanomaterials synthesized using different methods, highlighting their applications in biomedical and biological sciences, including bioimaging, biosensing, drug delivery, and therapeutics. Additionally, the impact of nanotechnology on precision agriculture is explored, showcasing recent advancements such as nanofertilizers, nanopesticides, nanobiosensors, and nanocarrier‐mediated delivery systems, which exhibit promising results. These recent developments underscore the transformative potential of nanotechnology in both biomedical and agriculture domains.

Recent Advances in Organic Molecular-to-Supramolecular Self-Assembled Room-Temperature Phosphorescent Materials for Biomedical Applications.

This minireview focuses on recent advancements in organic molecular-to-supramolecular self-assembled room-temperature phosphorescent (RTP) materials and their prospective biomedical applications. RTP materials, having their unique capacity to emit long-lasting phosphorescence at ambient temperature, have piqued researchers' interest in various biological applications, including biosensing, bioimaging, drug delivery, and photodynamic therapy (PDT). These materials have several benefits, including high sensitivity, remarkable photostability, and low cytotoxicity. RTP materials' self-assembly into supramolecular structures improves their performance and broadens their uses. Researchers have built organic RTP systems with long-lasting phosphorescence by leveraging weak noncovalent interactions in aquatic conditions. These materials have demonstrated incredible promise as biosensors that enable sensitive analyte detection and as photosensitizers in PDT that target and sensitize specific cell types. The review also outlines future directions and challenges in developing and utilizing pure organic RTP materials for biological imaging purposes, providing valuable guidelines for their future design and application.