Drug Delivery最新文献

As one of the most lethal gynecological malignancies, ovarian cancer (OC) significantly impacts the health and quality of life of women globally. Currently, surgical intervention and chemotherapy remain the primary clinical treatment modalities for OC. With ongoing advancements in the understanding of molecular mechanisms, various therapeutic strategies such as poly-ADP-ribose polymerase inhibitors (PARPi) treatment, immunotherapy, and combination therapies have also been introduced into clinical practice. However, significant challenges, such as systemic adverse effects, high recurrence rates, and the development of drug resistance, greatly limit their efficacy. To overcome these limitations, nanotherapeutics have emerged as promising multifunctional drug delivery systems for both the diagnosis and treatment of OC over the past few decades, owing to their ability to specifically target malignant tissues and enable controlled drug release. In this paper, we first review the tumor-targeting mechanisms of nanoparticles, which can guide researchers in designing suitable and effective nanomedicines with translational potential. We subsequently provide a detailed overview of several representative nanotherapeutic approaches used in the treatment of OC, including their roles in enhancing chemotherapy, PARPi therapy, immunotherapy, light- or ultrasound-mediated therapies, and various combination strategies. Finally, we discuss future perspectives and potential directions for nanotherapeutics in advancing personalized and targeted treatment of OC.

Apolipoprotein A-I (ApoA-I) mimetic peptides have garnered attention as potential anticancer agents owing to their role in cholesterol metabolism and ability to interact with the SR-BI receptor. However, their tendency to form lipid-bound structures in circulation limits their tumor-targeting therapeutic potential and raises the risk of off-target effects. In this study, we engineered a stimuli-responsive ApoA-I mimetic peptide by incorporating reactive oxygen species (ROS) -responsive amino acid derivatives into its sequence. Under normal physiological conditions, the peptide adopted a disordered conformation, minimizing nonspecific interactions. In contrast, the exposure to the tumor microenvironment, which is characterized by low pH and elevated ROS, could trigger a conformational transition to a structured α-helical state, thereby enhancing its membrane-disruptive and tumor-targeting capabilities. Molecular dynamics simulations predicted a rapid increase in α-helical content for the peptide candidate 5A under tumor-like conditions. These predictions were experimentally validated using circular dichroism spectroscopy, liposome leakage assays, and transmission electron microscopy, which demonstrated that peptide 5A effectively interacted with lipid membranes only upon activation in a tumor-like environment. In vitro cytotoxicity assays further confirmed the selective anticancer activity of peptide 5A under acidic conditions, while in vivo imaging and tumor inhibition studies in breast cancer models revealed significant tumor accumulation and a tumor growth inhibition rate of up to 71.43% at a 6 mg/kg dose. Our results demonstrated the potential of stimuli-responsive ApoA-I mimetic peptides for targeted cancer therapy, offering a promising strategy to enhance therapeutic efficacy while minimizing systemic toxicity.

Cancer is a complex disease characterized by uncontrolled cell growth and spread, often resulting in metastasis. The use of combination therapy, which involves the simultaneous application of two or more treatment methods, aims to enhance effectiveness and improve patient outcomes. This approach can enhance efficacy by targeting multiple mechanisms of cancer progression, leading to improved tumor response rates and survival. When combination therapy utilizes a codelivery platform, it enables dose reduction of each agent, thereby reducing side effects and increasing the therapeutic index. The simultaneous delivery of two or more drugs and therapeutic agents to solid tumors remains a major challenge in the development of more effective treatments. Polymersomes, owing to their unique and beneficial properties, are increasingly viewed as promising carriers for this purpose. They provide an excellent platform for combination therapies in cancer treatment. This review summarizes polymersome-based combination therapies, including chemotherapy, radiotherapy, antiangiogenic therapy, magnetic hyperthermia, dynamic therapy, starvation therapy, immunotherapy, photothermal therapy (PTT), and gene therapy. It also highlights recent advances and future prospects in polymersome-based combination cancer treatments. The aim of this study was to explore the challenges and opportunities in using polymersomes as drug codelivery vehicles, thereby enhancing our understanding of nanomedicine, especially in combination cancer therapies. Polymersome-based combination therapies have the potential to significantly transform current cancer treatments by enhancing accessibility, precision, and effectiveness while minimizing off-target effects.

CRISPR-Cas9 has revolutionized the field of genome editing. While conventional gene supplementation therapies and the market of related gene therapy products are dominated by viral vectors, non-viral delivery strategies are increasingly being explored for in vivo CRISPR applications. Given the permanent nature of genome editing, prolonged expression of the CRISPR machinery is not required, and transient delivery nevertheless can achieve lasting therapeutic effects. In contrast, short-term availability of genome editing components is rather considered advantageous to reduce the risk of off-target effects in a 'hit-and-run' fashion. In this article, we provide a systematic survey of the current clinical trial landscape with focus on in vivo CRISPR therapies and discuss utilized delivery strategies. As of December 2025, 136 CRISPR trials are ongoing, including 36 based on in vivo delivery of CRISPR components which show a clear shift towards non-viral vectors. The article describes the clinically employed CRISPR technologies and non-viral delivery platforms, highlighting both the present opportunities and key challenges associated with CRISPR delivery in the future.

Intestinal motility, including peristalsis and segmentation, drives complex fluid movements critical for the oral delivery of biologics and other macromolecules. Despite advances, oral delivery remains commercially limited by low bioavailability, often attributed to poor epithelial permeability. However, variability in motility patterns may also play a critical role, influencing intraluminal distribution and thus absorption, yet this aspect remains underexplored. Here, we combine computational fluid dynamics and machine learning to evaluate how motility type, intensity, pocket size, contractility, and fluid composition affect the delivery of a model macromolecule (insulin) and a permeation enhancer (sodium caprate, C10). We find that segmentation, especially at light intensity, consistently enhances epithelial colocalisation over peristalsis. Under segmentation, smaller pocket sizes (2 mL versus 10 mL) and stronger contractility (occlusion ratio 0.3) yielded optimal performance. Our extreme gradient boosting regression model identified pocket volume, contractility, and motility type as dominant predictors of colocalisation. In a comparative analysis, segmentation led to 128% and 137% higher maximum normalised concentrations of insulin and C10, respectively, than moderate peristalsis with a nutritional drink. Overall, segmentation achieved 6.7-fold and 8.0-fold higher average maximum normalised concentrations for insulin and C10, respectively. These results emphasise segmentation, characteristic of the fed state, as a superior motility pattern for macromolecular absorption compared to peristalsis during the migrating motor complex (MMC). By elucidating the interplay between motility and transport, our findings may guide the design of more effective oral formulations and support personalised strategies for drug delivery based on individual motility profiles.

Cardiovascular disease remains a leading cause of morbidity and mortality worldwide, posing a serious threat to human health. Atherosclerosis (AS), the pathological basis of most cardiovascular diseases, is characterized by arterial wall thickening caused by chronic inflammation. In recent years, molecular probes have attracted much attention as versatile tools for the diagnosis and treatment of AS, offering capabilities in imaging, drug monitoring, and surgical navigation. The existing probes include fluorescent probes, SERS probes, nuclear medicine probes, self-assembled nanoprobes, UC-FRET probes, photothermal probes, and multimodal probes. Among them, fluorescent probes have emerged as a research focus because of their excellent targeting effect, biocompatibility, and multimodal compatibility. This review summarizes recent advances in the classification and synthesis of fluorescent probes, their targeted applications in AS, and their auxiliary diagnosis and treatment of AS. By highlighting current progress and key challenges, this work aims to provide valuable insights to support further development and facilitate the advancement of fluorescent probe technologies in the context of AS, while promoting the clinical application of fluorescent probes.

Lymphatic transport of drugs after oral administration is an important physiological process in highly lipophilic compounds, such as cannabidiol (CBD). The majority of lymphatic transport studies have been historically conducted in anesthetized rats. However, this animal model differs significantly from the humans regarding both anatomical and physiological features. The aim of this study was therefore to develop a novel animal model using pigs and to provide an interspecies comparison for the lymphatic transport of CBD. The thoracic lymph duct was cannulated via thoracotomy in three pigs and lymph and blood were sampled from conscious animals to assess the lymphatic transport parameters and basic pharmacokinetic parameters of CBD administered in two distinct drug formulations (sesame oil-based solution and nanoemulsion) using a two-period cross-over study design. The mean ± SD oral bioavailability (F) was 6.1 ± 0.9% for the oil solution and 9.2 ± 6.6% for the nanoemulsion. The relative bioavailability via lymph (F_RL), i.e. the percentage of the systemically available drug that has been transported through the mesenteric lymph, was 20 ± 10% and 11 ± 13%, respectively. Whereas the F_RL for the oil solution was 2.3-fold lower in pigs compared to rats, the F_RL for the nanoemulsion was almost identical for both species. In conclusion, the lymphatic transport of CBD plays an important role after its oral administration. The particular parameters differed significantly between the rodent and higher non-rodent species. The use of higher species models is therefore warranted for the lymphatic transport assessment in settings close to humans.

The high selectivity of the vascular endothelium, exemplified by the blood-brain barrier (BBB), provides critical protection to tissues against harmful substances; however, it also severely restricts the targeted delivery of therapeutic agents, particularly large molecule drugs. Ultrasound-mediated microbubble cavitation has emerged as a promising strategy for enhancing drug delivery. However, conventional single-microbubble systems suffer from limitations, including uneven energy distribution and suboptimal permeabilization efficacy. Moreover, the synergistic mechanisms underlying dual-microbubble interactions within the microvasculature remain poorly understood. In this study, we developed a coupled two-microbubble fluid-solid system (TMFSS) model utilizing the finite element method to simulate the dynamic behavior of dual microbubbles within blood vessels under ultrasonic excitation. Our investigation focused on key parameters-including microbubble spacing, acoustic pressure amplitude, microbubble size, and shear-thinning blood rheology-and their effects on microbubble oscillation, microstreaming, vascular wall stress, and endothelial permeability. The results demonstrate that, compared with single-microbubble systems, the ultrasound-assisted TMFSS significantly enhances drug permeability. This synergistic permeabilization effect strongly depends on the acoustic parameters, blood viscosity, microbubble size, and spatial distribution. Our study quantitatively elucidates the structure‒activity relationship between TMFSS dynamics and drug penetration efficiency and presents a parameter optimization strategy for the precise modulation of vascular endothelial permeability.

Transcranial-focused ultrasound has demonstrated potential for blood-brain barrier (BBB) opening and localized drug delivery to intracranial brain lesions, making it a promising therapeutic strategy for glioblastoma (GBM) treatment. However, consistent drug delivery is hindered by cranial beam distortions, particularly standing-wave formation, when conventional sinusoidal-periodic ultrasound transmission sequences are used. We propose a novel Golay-coded random (Golay-random) ultrasound transmission sequence to mitigate standing wave effects and address this challenge. The efficacy of the Golay-random sequence was validated through computational simulations, which revealed significantly reduced pressure fluctuations compared to that in sinusoidal-periodic sequences. In vivo experiments quantified the BBB opening using gadolinium contrast-enhanced magnetic resonance imaging (MRI). The Golay-random sequence demonstrated effective BBB opening, with BBB permeability-increasing with burst length from 1.25 to 2.50 ms and plateauing at 5.00 ms. In contrast, no consistent correlation between burst length and BBB opening was observed with the sinusoidal-periodic sequence. In GBM mouse models, posttreatment MRI revealed significantly smaller tumor sizes in the group receiving doxorubicin with Golay-random transmission (G-Dox: 3.72 ± 4.34 mm³) compared to those with sinusoidal-periodic transmission (P-Dox: 18.05 ± 11.81 mm³). Optical in vivo imaging corroborated these findings, showing reduced tumor progression in the G-Dox group (4.54 ± 5.67) relative to the P-Dox group (25.17 ± 33.71). These results highlight the Golay-random sequence as a superior alternative to conventional sinusoidal-periodic sequences, offering improved precision and reliability in drug delivery and enhanced therapies for GBM.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer and is characterized by high invasiveness, rapid recurrence, and poor prognosis. To date, the ferroptosis-combined therapies have exerted their potential in the TNBC treatments via multi-mechanisms. Here, we reported a doxorubicin (DOX)-Fe complex and RSL3 co-loaded liposomes (DOX-Fe/RSL3@LIPs) for ferroptosis-enhanced chemotherapy on TNBC tumors. This nanoformulation performed a uniform spherical structure with a mean particle size of 126.9 nm, a zeta potential of -3.56 mV, and high colloidal stability. The pH-responsive dissociation of DOX-Fe and release of DOX were conducive to drug accumulation in the tumor microenvironment and tumor cells, meanwhile efficiently suppressed free DOX leakage in the blood circulation, potentially reducing the cardiotoxicity of DOX. In vitro cell and in vivo pharmacodynamic studies demonstrated a favorable anticancer effect of the DOX-Fe/RSL3@LIPs on 4T1 tumors by synchronously delivering biologically active DOX, Fe²⁺, and RSL3 to the tumor sites. DOX induced tumor cell death through a dual pathway of apoptosis/ferroptosis, and promoted the H₂O₂ generation. The tumor cell ferroptosis was observably enhanced via supplements of the ferrous ions and H₂O₂, and RSL3-derived GPX4 inhibition to severely destroy the oxidation balance in cells. In this paper, the DOX-Fe/RSL3@LIPs have exerted a synergistic anticancer effect on TNBC by combining ferroptosis and conventional chemotherapy, and made a meaningful exploration of new strategies for TNBC therapy.