Macromolecular drugs, due to their high specificity and excellent biological activity, play a crucial role in disease treatment. The oral administration route, with its advantages of high patient compliance and safety, is considered an ideal approach for delivering macromolecular drugs. However, various biological barriers in the gastrointestinal tract significantly limit the oral bioavailability and targeted delivery efficiency of macromolecular drugs. Existing research has primarily focused on overcoming single barriers or designing single carriers, this paper systematically addresses the multiple biological barriers encountered during the targeted delivery of orally administered macromolecular drugs. It provides an overview of various nanocarriers suitable for the targeted oral delivery of macromolecular drugs and delves into the latest advances in organ-specific targeting strategies, offering new perspectives for the precision treatment of orally administered macromolecular drugs. Furthermore, it incorporates examples of applications involving macromolecular drugs such as peptides, proteins, and nucleic acids, providing theoretical insights and research directions for enhancing the oral delivery efficiency of macromolecular drugs.

Aberrant activation of the phosphoinositide 3-kinase (PI3K)-AKT signaling pathway has been identified in numerous cancer types, contributing to uncontrolled cellular proliferation, inhibition of apoptosis, enhanced metastatic potential, and the development of resistance to chemotherapy and radiotherapy. Consequently, targeting the PI3K-AKT pathway has emerged as a promising therapeutic strategy. Current approaches to inhibit this pathway include small-molecule inhibitors, natural compounds, siRNAs, and miRNAs. However, these therapeutic approaches are often limited in clinical application due to prominent adverse effects, poor biological stability, low solubility, or lack of targeting ability. The integration of nanotechnology into drug delivery systems offers a compelling solution by improving drug stability and solubility, minimizing off-target accumulation, and enhancing tumor-specific targeting. Nanocarrier-based delivery of agents targeting the PI3K-AKT pathway holds the potential to improve therapeutic efficacy, mitigate drug-induced toxicity, sensitize tumors to conventional therapies, and ultimately enhance patient outcomes. This review provides a comprehensive overview of the PI3K-AKT signaling pathway and its oncogenic role, provides a detailed review of the latest progress of nano-based drug delivery system in cancer treatment based on pathways, and discusses future directions, aiming to inform and guide ongoing research in this field.

As a fundamental tool for enhancing ultrasound imaging contrast, ultrasound contrast agents (UCAs) have made significant advances in medical diagnosis and therapeutics in recent years. Their development has processed through four generations, with each generation achieving breakthroughs in core gas composition, shell materials, stability, and clinical applicability. The imaging mechanism of UCAs is based on the interaction between microbubbles and ultrasound waves, producing enhanced backscatter to generate clearer images. The in vivo behavior of microbubbles is influenced by various physiological factors. Both the core gas and shell materials are ultimately metabolized or safely eliminated from the body. Common preparation methods include ultrasonic cavitation, high-shear processing, mechanical agitation and so on. In modern medical applications, UCAs are widely employed in the diagnostic imaging of the heart, liver and tumors. Moreover, through targeted ligand modification and drug-loading strategies, they offer potential for theranostic application, i.e., integrating diagnosis and treatment. UCAs can also provide unique therapeutic benefit through gas-mediated therapies. This review systematically presents the development history of UCAs, elaborating on their imaging mechanisms, in vivo behavior, preparation techniques, physicochemical characteristics, and emerging applications at diagnostic-therapeutic interface.

Microalgae, as a class of photosynthetic microorganisms, possess excellent biocompatibility and metabolic diversity. They are capable of synthesizing various natural products with antioxidant, immunomodulatory, and anticancer activities, while also demonstrating great potential as drug delivery vehicles. Their inherent properties — such as self-propelled motility, photosynthetic oxygen generation, and biodegradability — facilitate enhanced accumulation of therapeutics within tumor tissues and improve treatment efficacy. However, natural microalgae still face limitations in targeting ability and drug loading capacity, necessitating engineering strategies to meet the complex demands of cancer therapy. This review summarizes representative microalgal species, their structural features, and biomedical applications. It further provides a systematic overview of current engineering approaches, including physical interactions, chemical modifications, biomembrane coatings, and genetic engineering. Particular attention is given to their emerging roles in multimodal tumor therapies, such as photoresponsive, magnetically guided, and immuno-combined treatment platforms. Finally, future development directions and prospects for clinical translation are discussed.

Nanocarriers, have been extensively explored as a novel drug delivery system, demonstrating significant advantages in improving drug solubility, stability, and targeting capability, and have thus become a research focus in the field. However, their clinical application is substantially limited by a poor capacity to traverse cellular membranes and overcome complex physiological barriers. Cell-penetrating peptides (CPPs), characterized by high membrane penetration efficiency, low toxicity, and favorable biocompatibility, can effectively facilitate the translocation of nanocarriers across biological membrane barriers via direct penetration or endocytosis, thereby significantly enhancing drug delivery efficiency. Concurrently, homing peptides (HPs) enable precise accumulation of nanocarriers at pathological sites by recognizing tissue-specific receptors, while reducing non-specific penetration into healthy tissues. As two crucial classes of functional peptides, CPPs and HPs have been widely utilized to modify nanocarriers, enhancing their capacity to overcome physiological barriers and improving targeted accumulation at diseased sites through distinct mechanisms. This review summarizes the classification and transport mechanisms of CPPs and HPs, as well as advances in their application for modifying nanocarriers to overcome physiological barriers, aiming to provide a reference for future research and applications in this field.

Plant-derived nanovesicles are nano-sized extracellular vesicles that encapsulate nucleic acids, proteins, and lipids, and exert antioxidant, anti-inflammatory, antitumor, and tissue-regenerative effects, showing great potential for disease intervention. Schisandra chinensis (Turcz.) Baill., a traditional medicinal plant, has been extensively studied by our group and others for its hepatoprotective constituents and mechanisms of action. Excessive acetaminophen (APAP) intake is the leading cause of drug-induced liver injury in clinical practice, yet effective and low-toxicity preventive or therapeutic strategies are still lacking. To investigate the protective effect and mechanism of Schisandra chinensis-derived nanovesicles (SSDNs) against APAP-induced acute liver injury in mice, SSDNs were first isolated from Schisandra chinensis by gradient ultrahigh-speed centrifugation. Transmission electron microscopy and nanoparticle tracking analysis revealed an exosome-like bilayer membrane, uniform morphology, and a mean diameter of 205.4 nm. In vitro CCK-8 assays showed that SSDNs exhibited no cytotoxicity. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis identified schisandrol A as the major lignan component of SSDNs. Furthermore, we evaluated the protective effect of SSDNs on APAP-induced acute liver injury in mice. All experimental protocols were approved by the Animal Ethics Committee of Southern Medical University (approval No. SMUL202408016). C57BL/6 mice were pretreated with SSDNs via tail vein injection for 4 days and then given a single intraperitoneal injection of APAP (400 mg·kg^-1). Pretreatment with SSDNs significantly lowered serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, reduced hepatic necrosis, and restored lobular architecture. Concurrently, SSDNs elevated the hepatic glutathione (GSH) level, decreased protein expression of APAP-metabolizing enzymes cytochrome P450 (CYP) 2E1 and CYP3A11, and upregulated proliferating cell nuclear antigen (PCNA) and cell-cycle proteins [cyclin-dependent kinase 4 (CDK4), cyclin A1 (CCNA1), cyclin D1 (CCND1), and cyclin E1 (CCNE1)]. In conclusion, SSDNs mitigate APAP-induced acute liver injury in mice by preserving hepatic GSH, suppressing CYP450 enzymes involved in APAP metabolic activation, and promoting hepatocyte proliferation and repair. These findings offer a novel strategy for the modern application of Schisandra chinensis and the clinical prevention of APAP-induced hepatotoxicity.

Based on the traditional Chinese medicine theory that "excessive Qi transforms into fire", this study investigates whether overdose of the Qi-tonifying herb Astragalus membranaceus (AM) induces "Shanghuo" and analyzes the related components and underlying mechanisms. Using a mouse model of "Shanghuo" with latent herpes simplex virus type 1 (HSV-1) infection, we systematically observed the general state and behavioral changes of the mice, and detected the expression of virus-related genes and proteins as well as lipid peroxidation-related indicators. The results showed that after intervention with AM and its components, the mice exhibited various "Shanghuo" symptoms, including eye inflammation, increased thirst and water intake, dry stool, and hyperactivity. These symptoms were accompanied by reactivation of latent HSV-1 in the brain, upregulation of lipid peroxidation-related proteins arachidonate 15-lipoxy-genase (ALOX15) and 4-hydroxynonenal (4-HNE), downregulation of cluster of differentiation 117 (CD117; c-Kit) protein expression in intestinal tissue, and elevated levels of the lipid peroxidation product 4-HNE. Further component analysis revealed that AM polysaccharides had a particularly significant impact on behavioral indicators, while low-content AM isoflavones and saponins also reactivated latent HSV-1. In conclusion, various components of AM may synergistically reactivate latent HSV-1 and induce "Shanghuo" potentially through enhancing lipid peroxidation in the body.This experiment has been approved by the Animal Experimental Ethics Committee of Jinan University (IACUC-20250417-04).

Osimertinib, as a first-line therapeutic agent for non-small cell lung cancer (NSCLC), significantly prolongs patients' progression-free survival and overall survival. However, the development of acquired resistance to this agent remains an unavoidable clinical challenge. This study investigated platycodin D (PD) as a potential resistance modulator. Cell viability was assessed using the CCK-8 assay; cell proliferation was detected using the colony formation assay; cytotoxic effects were evaluated via lactate dehydrogenase (LDH) release; apoptosis was detected by PI/Hoechst double staining and flow cytometry; and the expression of apoptosis-related proteins and key components of the Akt/p70S6K pathway as well as phosphorylation levels were examined by Western blot. Results demonstrated that platycodin D suppressed the viability of osimertinib-acquired resistant NSCLC cells and exhibited synergistic antiproliferative effects when combined with osimertinib. The combination treatment significantly inhibited cell growth and induced apoptosis, with effects markedly stronger than either agent alone. Mechanistic studies revealed that the combined treatment more effectively suppressed the phosphorylation of Akt and p70S6K as compared to the single treatment group. In conclusion, this study reveals that platycodin D can enhance the cytotoxic effect of osimertinib against resistant NSCLC cells and reverse osimertinib resistance by inhibiting the Akt/p70S6K signaling pathway, thereby providing a promising strategy to overcome osimertinib resistance.

This study aims to investigate whether Xiaoxianxiong Decoction (XXXD) can exert a protective effect in atherosclerosis (AS) by activating growth arrest specific 6 (GAS6)/receptor tyrosine kinase AXL (AXL) and inhibiting endothelial cell ferroptosis. This experiment was approved by the Animal Experiment Ethics Committee of Shaanxi Academy of Traditional Chinese Medicine (approval number: 2022-10). At the animal level, the apolipoprotein E knockout (ApoE^-/-) mice were fed with a high-fat diet (HFD) to establish the AS model. At the cellular level, the endothelial cell injury model was established with oxidized low-density lipoprotein (ox-LDL), and the cell viability, lactate dehydrogenase (LDH), reactive oxygen species (ROS), Fe²⁺, and lipid peroxidation indicators malondialdehyde (MDA), superoxide dismutase (SOD), total glutathione peroxidase (GPx), and glutathione reductase (GR) were detected. Western blot was used to detect the expression of GAS6, AXL, glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) proteins. The results showed that XXXD could reduce body weight, aortic plaque area and lipid accumulation in AS mice, improve dyslipidemia, increase lipid antioxidant capacity in aorta and endothelial cells (increase SOD, GPx and GR, inhibit MDA), reduce LDH, ROS, MDA and Fe²⁺ levels in endothelial cells, and up-regulate the expression of GAS6, AXL, GPX4, and SLC7A11 proteins to improve AS and endothelial cell injury. The above results confirmed that XXXD can alleviate AS by regulating ferroptosis of endothelial cells through the GAS6/AXL signaling pathway.

This study aims to explore the therapeutic effect and mechanism of action of Zhisou Huatan Wan on rats with chronic obstructive pulmonary disease (COPD) of phlegm-heat obstructing the lungs. Animal experiments were approved by the Experimental Animal Ethics Committee of Henan University of Chinese Medicine (approval number: IACUC-202506002). Sixty male SD rats were randomly divided into six groups: control group, model group, erythromycin group (100 mg·kg^-1), and low-dose (206.55 mg·kg^-1), medium-dose (413.1 mg·kg^-1), and high-dose Zhisou Huatan Wan (826.2 mg·kg^-1) group. The rats were constructed with COPD of phlegm-heat obstructing the lungs by using smoke inhalation combined with intratracheal injection of lipopolysaccharide (LPS, 1 mg·kg^-1) and cold air stimulation. The lung function, cough frequency, tracheal phenol red excretion, the degree of pulmonary tissue edema, arterial partial pressure of oxygen (PaO₂), arterial partial pressure of carbon dioxide (PaCO₂) of each group of rats were detected. H & E, Masson, and PAS staining were used to detect lung tissue lesions. The levels of apoptosis, oxidative stress and mitochondrial membrane potential in lung tissue, and peripheral blood immune cells (neutrophils, Treg cells, Th17 cells) were detected by flow cytometry. Transcriptomics analysis was used to screen core targets and signaling pathways. ELISA was applied to measure the levels of interleukin 17A (IL-17A), C-C chemokine ligand 7 (CCL7) and C-C motif chemokine ligand 20 (CCL20) in serum and lung tissue. qRT-PCR was used to detect the mRNA levels of IL-17A, CCL7 and CCL20 in lung tissue. IL-17A protein level was detected by Western blot. The results showed that Zhisou Huatan Wan significantly improved lung function, increased the level of blood oxygen partial pressure, mitochondrial membrane potential in lung tissue, and Treg cells in peripheral blood, promoted tracheal phenol red secretion, alleviated pathological lung injury, and reduced cough frequency, carbon dioxide partial pressure, the degree of pulmonary tissue edema, apoptosis and oxidative stress levels in lung tissue, as well as the levels of neutrophils and Th17 cells in peripheral blood. Zhisou Huatan Wan reduced the content of IL-17A, CCL7 and CCL20 in serum and lung tissue, and the corresponding mRNA levels in lung tissue, as well as the expression level of IL-17A in lung tissue. Transcriptomic analysis identified 78 differentially expressed genes, and primarily enriched in IL-17 signaling pathway, the chemokine signaling pathway and cytokine-cytokine receptor interaction. The results showed that Zhisou Huatan Wan had a significant improvement effect on COPD rats of phlegm-heat obstructing the lungs, and its mechanism may be related to the IL-17 signaling pathway.