Precision nanomedicine has long been driven by the pursuit of spatial targeting, enabling therapeutic agents to reach specific tissues, cells, and subcellular compartments. However, therapeutic efficacy depends not only on where drugs act, but also on when they act. In cancer immunotherapy, immune activation follows a coordinated temporal sequence, creating distinct therapeutic windows for different interventions. Despite this, most nanomedicine strategies continue to optimize tumor accumulation while paying little attention to the timing of drug release relative to biological processes. Here, we propose temporal programming as a new design principle for precision nanomedicine, in which release kinetics are engineered to align with disease biology. We discuss how integrating temporal programming with spatial targeting may provide a conceptual framework for next-generation nanomedicine and improve the design of future cancer immunotherapies.
IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is characterized by mesangial IgA deposition, which triggers complement activation, primarily through the alternative pathway. While complement dysregulation contributes to kidney injury and adverse outcomes, complement may also facilitate clearance of pathogenic immune complexes. Here, we compared complete complement component 3 (C3) deficiency with supplementation of complement factor H (Cfh), the principal regulator of alternative pathway, in murine IgAN models. C3 deficiency prevented complement activation but paradoxically increased glomerular IgA deposition and macrophage infiltration, resulting in complicated inflammatory response. In contrast, Cfh supplementation reduced glomerular IgA and C3 deposition, decreased inflammatory cytokine expression, attenuated macrophage infiltration, lessened glomerular area and ameliorated proteinuria while enhancing macrophage-mediated phagocytosis of circulating IgA immune complexes. Accordingly, IgAN patients with higher plasma CFH levels exhibited reduced mesangial IgA and C3 deposition alongside elevated circulating C3 levels, supporting CFH’s protective role in regulating complement activation and promoting immune complex clearance. Our results reveal complement’s dual role in IgAN: promoting inflammatory kidney injury while facilitating clearance of pathogenic IgA deposits. Targeted complement regulation via complement factor H supplementation, rather than complete complement inhibition via global complement component 3 knockout, achieves superior therapeutic effects by simultaneously controlling complement activation, enhancing immune complex clearance, suppressing inflammation, and reducing proteinuria. These findings identify complement factor H as a novel and promising therapeutic strategy for IgA nephropathy through targeted complement regulation.
Neurovascular coupling (NVC) reflects the coordination between brain activity and cerebral blood flow, while glymphatic function indicates the capacity to clear metabolic waste from the brain. However, differences in these two factors between patients on peritoneal dialysis (PD) and hemodialysis (HD), as well as their interrelationship, remain unclear. Functional magnetic resonance imaging, three-dimensional pseudo-continuous arterial spin labeling, and diffusion tensor imaging were prospectively performed in 56 patients on PD, 54 patients on HD, and 52 healthy controls (HC). The study calculated the amplitude of low frequency fluctuation-cerebral blood flow (ALFF-CBF) coupling coefficient and the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, which respectively represent the overall NVC level and the glymphatic function. Compared to HC, patients on PD and HD exhibited lower ALFF-CBF coupling coefficients and DTI-ALPS indices, but there were no significant differences between the PD and HD groups. Additionally, positive correlations were observed between ALFF-CBF coupling coefficients and DTI-ALPS indices across all three groups. he degrees of neurovascular decoupling and altered glymphatic function are comparable between patients on PD and HD. Importantly, neurovascular decoupling may be associated with altered glymphatic function in patients on dialysis. The degrees of neurovascular decoupling and altered glymphatic function are comparable between patients on PD and HD. Importantly, neurovascular decoupling may be associated with altered glymphatic function in patients on dialysis.
Despite the European Alliance of Associations for Rheumatology (EULAR) recommendation to minimize glucocorticoid (GC) use in systemic lupus erythematosus (SLE), prospective data quantifying toxicity across low-dose ranges are lacking. This study aimed to assess toxicity using the GC toxicity index (GTI) in SLE patients and compare toxicity profiles among dose-defined subgroups. Patients from the STAR cohort (May 2023–May 2024) were prospectively followed up for 1 year. Stratified by average daily prednisone (PDN) dose, toxicity was assessed using GTI comprising the aggregate improvement score (AIS) and the cumulative worsening score (CWS) at baseline and 1 year. Three pre-planned stepwise comparisons used dose thresholds of 7.5 mg, 5 mg, and 2.5 mg, with a Bonferroni-corrected significance level of P < 0.0167 (α = 0.05/3). Quantile regression evaluated the association between average daily PDN dose and CWS/AIS. Of 302 patients, the PDN ≤ 7.5 mg/day group (n = 223) showed statistically lower median CWS [0 (IQR 0–19) vs. 48 (IQR 19–84), P < 0.001] and AIS [0 (IQR − 19–10) vs. 40 (IQR 9–74), P < 0.001] compared to the PDN > 7.5 mg/day group (n = 79). Within the low-dose group, patients with 5 < PDN ≤ 7.5 mg/day (n = 52) exhibited higher median CWS [10.5 (IQR 0–29) vs. 0 (IQR 0–19), P = 0.002] and wider AIS interquartile range [0 (IQR − 18.75–29) vs. 0 (IQR − 20–0), P = 0.010] than the PDN ≤ 5 mg/day subgroup (n = 171). No significant differences in CWS or AIS were observed between the PDN ≤ 2.5 mg/day (n = 90) and 2.5 < PDN ≤ 5 mg/day (n = 81) subgroups. Quantile regression indicated that each 1 mg/day increase in PDN dose raised median CWS by 3.33 points and median AIS by 3.42 points. To our knowledge, this study provided the first prospective and quantitative evidence using the GTI to demonstrate that PDN dose reduction to ≤ 5 mg/day was linked to reduced toxicity. Moreover, we found that no dose was entirely safe, which strongly supported the EULAR strategy of rigorous GC minimization.
Recombinant human growth hormone (rhGH) treatment for idiopathic short stature (ISS) in China faces challenges including delayed initiation, poor persistence, limited adoption of advanced therapies, and conservative dosing. This study characterized real-world temporal and geographical patterns of rhGH therapy and identified associated socioeconomic factors. Data from two nationwide registries comprising 24,384 children with ISS initiating rhGH were analyzed. Predictors of treatment effectiveness were identified via linear regression. Provincial variations and temporal trends were assessed via descriptive analysis and seasonal-trend decomposition. Spearman correlation was used to examine associations between treatment patterns and socioeconomic indicators. The median rhGH initiation age was 8.45 years. Most patients (81.3
