Bo Zhang

RNA therapeutics offer considerable potential for cancer treatment. Their therapeutic application, however, remains limited by rapid degradation, inefficient cellular uptake, and restricted intracellular release. Extracellular vesicles (EVs) are cell-derived membrane vesicles that have been exploited as promising vehicles for drug delivery due to their high biocompatibility and low immunogenicity, whereas liposomes and lipid nanoparticles provide tunable lipid composition and efficient loading of exogenous nucleic acids. Combining these carriers has led to EV–lipid hybrid systems designed to integrate their complementary properties. This review summarizes recent advances in EV–lipid hybrids for cancer therapy and organizes the reported systems according to their structural architecture and preparation. EV–liposome fusion hybrids, EV–lipid nanoparticle hybrids, and EV membrane-integrated lipid nanocarriers are discussed in relation to their RNA-loading strategies and representative therapeutic designs. The review also examines the key processes involved in functional RNA delivery and summarizes representative applications across different cancer types. Challenges associated with safety evaluation are also discussed, together with future directions for clinical translation. Overall, EV–lipid hybrids represent a promising strategy for RNA-based cancer therapy.

Exosomes have become one of the hotspots in life science research in recent years. As an important carrier of bio-information substances, they can mediate intercellular communication by carrying various bioactive substances, thereby activating specific signal transduction pathways within cells and ultimately regulating cell phenotypes and functions. Among the abundant cargoes carried by exosomes, drug-metabolizing enzymes have gradually attracted increasing attention from researchers. More and more evidence suggests that the abundance and activity levels of these specific drug-metabolizing enzymes encapsulated in exosomes can often reflect the dynamic gene expression in their parent cells, which is of great significance for studying inter-individual variability in drug exposure. Based on this, this article reviews the biological origin of exosomes, related regulatory programs, their potential as biomarkers indicating in vivo drug exposure, and related research results in the above fields in recent years, aiming to deepen the understanding of the role of exosomes in drug metabolism and provide more reference for future research on individualized drug administration of exosomes.

Background: Over the past approximately 40 years, Chinese drug regulations have undergone many major reforms to accelerate the approval of drugs and keep pace with the scientific innovation of drugs in the world, especially developed countries. In 2018 and 2023 China’s National Health Commission in collaboration with other departments released China’s “First Batch of Rare Diseases Catalogue” and “Second Batch of Rare Disease Catalogue”. However, there is currently less relevant research on the overview and speed of the approval of rare disease drugs in China. Methods: This study used cross-sectional analysis of rare disease drugs approved in China and the USA from 1983 to 2022 through official drug search databases and systematically analyzed and compared rare disease drugs approved in the USA and China, including the number, approval time, related laws and regulations, and expedited programs. Results: Between 1983 and 2022, the USA Food and Drug Administration (FDA) approved a total of 693 orphan drugs (covering 1228 formulations/specifications). Among these, 201 drugs (425 formulations/specifications) were approved by China’s National Medical Products Administration (NMPA), accounting for 29.0% (201/693) of the approved drugs and 34.6%(425/1228) of the approved formulations/specifications. The number of China’s rare diseases drugs is increasing year by year, and the approval speed has gradually accelerated. The median approval lag time was 32.3 years (IQR: 22.9–33.6) from 1983 to 1987. In contrast, the shortest median lag time occurred between 2018 and 2022, at approximately 1.4 years (IQR: 0.5–2.6)—a reduction of 94.2% that reflects the success of China’s ongoing drug regulatory reforms. The special procedures for drug approval have a great promoting effect on rare diseases drugs’ approval. Conclusion: This research provides evidence of breakthroughs in the review and approval of rare disease drugs in China and demonstrates the tremendous boost to rare disease drugs from China’s ongoing restructuring and reform of the drug regulatory ecosystem, as well as a stimulus for future rare disease drugs development in China.

This study aims to describe the demographic, laboratory, and clinical characteristics of systemic sclerosis (SSc) patients in a Chinese national tertiary referral center, and to outline the treatment model. A retrospective observational study was conducted on adult SSc patients admitted to Peking Union Medical College Hospital between January 2012 and January 2022. Data were collected from electronic medical records, including demographics, clinical, laboratory parameters, and treatment details, and analyzed using SPSS. This study included 232 SSc patients, with 45.7% classified as diffuse cutaneous SSc (dcSSc) and 54.3% as limited cutaneous SSc (lcSSc). Anticentromere antibody and anti-topoisomerase I antibody were more common in lcSSc (33.3%) and dcSSc (36.2%), respectively. Excluding skin manifestations, the most common organ involvement was gastrointestinal, particularly esophageal involvement (56.5%), followed by diastolic dysfunction (53.2%), pericardial effusion (48.9%), pulmonary arterial hypertension (PAH) (44.8%), and lung fibrosis (20.1%). Combined immunosuppressive therapy was common, with 85.1% and 51.8% of patients receiving glucocorticoids and cyclophosphamide, respectively; medications for complication management, such as proton pump inhibitors (64.5%) for gastrointestinal involvement, were also frequently prescribed. Additionally, traditional Chinese medicine was incorporated into the regimen for almost one-quarter (23.7%) of patients. Multivariate analysis revealed that elevated N-terminal pro-brain natriuretic peptide and elevated C-reactive protein were significantly associated with PAH (OR = 12.359 and 3.239). This study delineates a clinical profile of Chinese SSc patients characterized by frequent multi-organ involvement and a common practice of combined immunosuppressive therapy. Further exploration is needed to develop more precise pharmacological strategies and to identify predictive factors for SSc-related complications.

Objectives: This study explored the health-related quality of life (HRQoL), psychological health, and patient-reported outcomes (PROs) of patients with amyotrophic lateral sclerosis (ALS) in China, providing insights for enhancing clinical care. Methods: A cross-sectional study was conducted among Chinese ALS patients between February and May 2024. Demographics, clinical characteristics, and PROs were assessed. HRQoL and psychological health were evaluated via the 5-item amyotrophic lateral sclerosis assessment questionnaire (ALSAQ-5) and the 4-item patient health questionnaire (PHQ-4), respectively. Spearman’s rank correlation, multiple linear regression, and the Kruskal–Wallis H test were used to analyze associations between clinical factors, HRQoL, and psychological health. Results: A total of 237 participants aged 46–65 years (63.3%) were included. The mean ALSAQ-5 score was 64.86±19.34, indicating an impaired HRQoL, whereas the mean PHQ-4 score (5.82 ± 4.10,) suggested varied degree of anxiety and depression. Age, disease duration, ALS severity, fatigue, stress, and pain severity, and respiratory support were significantly associated with HRQoL (p < 0.05). Age, stress severity, and pain severity were significant predictors of psychological distress (p < 0.01). Patients reported diagnostic delay, profound lifestyle changes (96.4%), fear of paralysis (84.8%), and death (49.8%). Most patients (80.6%) expressed a strong desire to stop ALS progression, prioritizing treatments that improve breathing, muscle weakness, swallowing, and mobility issues. Conclusions: ALS profoundly impacts patients’ HRQoL and psychological health. Integrating PROs into clinical care strategies is crucial for improving patient outcomes and guiding treatment priorities.

Nusinersen is the first antisense oligonucleotide (ASO) drug approved for the treatment of spinal muscular atrophy (SMA) in China; however, its pharmacokinetics (PK) in Chinese SMA patients remains unknown. The objective of this study was to develop and validate a liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) methodology for quantifying nusinersen in human plasma and cerebrospinal fluid (CSF) samples. The samples were prepared by protein precipitation, and then the gradient was eluted on a column of Acquity UPLC Xbridge C18 by using acetonitrile with 0.5% triethylamine (TEA) and 0.5% hexafluoroisopropanol (HFIP) and water with 0.5% TEA and 0.5% HFIP as the mobile phase. Detection was performed on a QTRAP6500⁺ tandem mass spectrometer in the negative ion multiple reaction monitoring (MRM) mode using electrospray ionization (ESI). The optimized method was successfully qualified for the nusinersen in human plasma and CSF samples over the range of 5.00 to 1000 ng/mL and 2.00 to 400 ng/mL, respectively. Importantly, our work is the first report of quantification of nusinersen in human plasma and CSF by LC–MS/MS methodology. The developed methodology is reliable and will be applied to PK study of nusinersen in Chinese SMA patients.

Background: Achieving pharmacokinetic/pharmacodynamic (PK/PD) targets is critical for improving treatment success, particularly in critically ill patients. This study investigates the role of inflammatory biomarkers and their influence on the PK/PD characteristics of polymyxin B (PMB) in patients with extensively drug-resistant Gram-negative (XDR-GN) bacterial nosocomial pneumonia. Methods: Serial blood and/or bronchoalveolar lavage fluid (BALF) samples were collected at specified time points and analyzed for PMB and/or inflammatory biomarkers, including IL-6 and IL-10. Clinical data were also recorded, and their correlations with PK parameters were further analyzed. Results: Among the 27 enrolled patients, 22 (81.5%) achieved treatment success. The pharmacokinetic parameters of PMB included a maximum plasma concentration (C_max) of 8.3 µg/mL, clearance (CL) of 1.55 L/h, volume of distribution (Vd) of 30.44 L, half-life (t_1/2) of 19.56 h, steady-state area under the plasma concentration–time curve from time 0 to 24 h (AUC_ss,0–24h) of 110.08 h·µg/mL, and a plasma protein-binding ratio of 85.53%. The AUC_ss,0–24h metric was identified as a robust predictor of clinical efficacy, with an optimal cutoff value of 77.27 h·µg/mL. Notably, 48.15% of patients achieved the target AUC_ss,0–24h range of 50–100 h·µg/mL, with 76.95% of these patients attaining treatment success. Another 48.15% of patients exceeded this target, and 92.31% of this subgroup achieved treatment success. PMB demonstrated limited pulmonary penetration, with an epithelial lining fluid (ELF)/plasma ratio of 15.69% [16.86, 18.15]. Furthermore, TNF-α and the IL-6/IL-10 ratio were significantly correlated with PMB PK parameters. Conclusions: Our and others’ studies suggest heterogeneity of PMB PK parameters in critically ill patients. The majority of critically ill patients achieved or surpassed the recommended PK/PD targets and attained treatment success through intravenous administration of PMB at a simplified fixed dose. However, PMB did not achieve satisfactory pulmonary concentrations, suggesting that its efficacy may involve alternative mechanisms. The modulation of inflammatory responses may play a pivotal role in the treatment of severe infections, highlighting the potential for biomarker-guided therapeutic strategies.

Purpose Systemic sclerosis (SSc) is a chronic connective tissue disorder characterized by skin thickening with vascular and visceral involvements. The efficacy of cyclophosphamide for SSc-related skin fibrosis remains controversial. The aim of this study was to evaluate the effectiveness of cyclophosphamide for skin fibrosis in SSc. Methods PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov databases were systematically searched for all published clinical trials on the treatment of SSc with cyclophosphamide until January 15, 2025.The outcome of interest was the extent of skin fibrosis, measured by the modified Rodnan skin score (mRSS). Two authors independently screened studies, extracted data, and evaluated the risk of bias. Meta-analysis was conducted with Stata/SE software. Results A total of 20 articles involving 869 patients met the inclusion criteria. Cyclophosphamide reduced mRSS score by 2.30 (95% CI 0.72–3.88), 4.53 (95% CI 2.91–6.14), 6.72 (95% CI 2.74-10.70), 5.70 (95% CI 4.04–7.36), and 4.60 (95% CI 3.18–6.02) at 6-, 12-, 18-, 24- and 36-month, respectively. The estimated effect size, obtained by pooling mRSS from all studies at the follow-up endpoint, decreased by 4.71 (95% CI 2.72–6.70). In diffuse cutaneous SSc (dcSSc) subtype, the pooled mRSS decreased by 3.02 (95% CI 1.46–4.58), 6.45 (95% CI 5.02–7.87), 8.03 (95% CI 5.26–10.80), and 6.34 (95% CI 6.00–6.68) at 6-, 12-, 18-, and 24-month, respectively. And the overall reduction in mRSS at the end of follow-up in dcSSc was 7.30 (95% CI 5.61–8.99) across 11 studies. Significant heterogeneity was observed among these studies, and subgroup analysis revealed that study size and disease subtype partially explained the heterogeneity. Sensitivity analysis indicated good study stability. Conclusion Cyclophosphamide effectively reduced mRSS scores in SSc, particularly in dcSSc. While skin thickness improvement diminishes after 24 months, it remains a viable option for patients with worsening skin fibrosis. Trial registration PROSPERO registration number: CRD42024502283. Registered on 25 January 2024.