间质性膀胱炎膀胱疼痛综合征（Interstitial Cystitis/Bladder Pain Syndrome, IC/BPS）是一种特征表现为膀胱超敏、尿频尿急及慢性盆腔疼痛的泌尿系统疾病，目前病因不明。现有治疗手段包括口服药物、膀胱灌注及手术干预。然而，由于泌尿系统特殊的解剖结构，传统口服或静脉给药常受首过效应、全身暴露量高及靶组织浓度不足等因素限制，治疗效果往往不佳。相比之下，膀胱内给药可提高药物局部浓度，弥补全身给药的不足，但仍面临局部滞留时间短、生物利用度低及患者依从性差等问题，导致疗效受限。近年来，局部靶向递送技术成为研究热点，其中磷脂基辅料凭借其优异的生物相容性、类细胞膜结构及增溶特性，被广泛用于改善难溶性药物的跨膜渗透与组织滞留。然而，膀胱内复杂的生理环境（如尿液冲刷、黏液屏障）对纳米制剂的稳定性与黏附性提出了更高要求，亟需通过功能化修饰优化递送系统性能。

连翘苷（Forsythin）是中药连翘的主要活性成分之一，具有抗炎、抗病毒及抗氧化作用，可降低白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）等促炎因子表达，同时清除活性氧（ROS）缓解氧化应激损伤。但因其水溶性差、口服生物利用度低，在IC/BPS治疗中的应用被限制。本研究基于纳米递送技术，构建了连翘苷磷脂复合物（FPC）及固体脂质纳米粒（FOS、FPS），并进一步开发壳聚糖修饰的磷脂复合物（CTS-FPC），以提高药物的局部滞留与缓释性能，为IC/BPS的治疗提供新策略。

首先，本研究对比了两种主流建模策略：膀胱灌注脂多糖（LPS）+硫酸鱼精蛋白（PS）法及腹腔注射环磷酰胺（CYP）法，并通过病理学检测、炎症因子分析及组织学评价筛选出稳定可靠的造模方案。结果显示，CYP诱导模型能够梯度式模拟急性、亚急性及慢性炎症表型，为后续药效评价提供了可靠平台。

在IC模型基础上，本研究进一步开展了潜在治疗药物的筛选。首先评估了磷酸二酯酶-4（PDE-4）抑制剂（dm0420、罗氟司特）及硫酸软骨素类似物（CS、PACS）对膀胱炎症屏障的修复作用。实验结果表明，PDE-4抑制剂可以有效改善屏障完整性，而硫酸软骨素类似物在治疗性给药中表现出黏膜保护效应，但预防性效果有限。在此基础上，以连翘苷为负载药物进一步构建FPC、FOS及FPS，并利用红外光谱（FTIR）、差示扫描量热法（DSC）、粒径及Zeta电位分析等方法对其进行理化表征。体外释放结果显示，FPC能够显著提高连翘苷的水溶性和跨膜渗透能力，相较于游离连翘苷，其6 h累积释放率提高至82.97%。相比之下，FPS进一步优化了药物在膀胱中的释放行为，展现出缓释特性，24 h累积释放率降至65.38%，有效延长了药物的作用时间。药效实验显示，FPS可以显著降低动物膀胱组织中IL-6与TNF-α的表达水平，且疼痛评分具有统计学差异，提示其具备良好的抗炎及镇痛效果。膀胱内递送实验进一步证实，FPS组大鼠膀胱组织AUC较游离连翘苷提高6.9倍，T_1/2从0.54 h延长至8.27 h，在提高生物利用度的同时增强了药物的缓释效果。

为进一步延长膀胱内滞留时间，减少给药频次以提升患者依从性，本研究引入阳离子多糖壳聚糖（CTS）对FPC进行表面修饰，构建CTS-FPC纳米递送系统。结果显示，相比于FPC，CTS-FPC的粒径略增，Zeta电位由负变正，在慢性IC模型中表现出优异的抗炎效果。药效实验结果显示，其能够显著降低Evans Blue渗透量（P<0.0001），缓解膀胱水肿与自发性疼痛，降低炎症评分（P<0.001）以及IL-6及TNF-α的表达水平。小动物活体成像实验和组织学分布进一步证实，CTS-FPC可在膀胱组织中持续滞留96 h，具有优异的黏膜粘附性和缓释特性。

综上，本研究成功构建了基于连翘苷的纳米递送系统，并优化了其缓释性能与抗炎药效。FPC提高了连翘苷的生物利用度，FPS通过缓释机制延长了药物作用时间，而CTS-FPC进一步增强了膀胱内滞留能力，实现了“长效-高效”治疗目标。研究结果表明，该连翘苷纳米递送系统在改善IC/BPS的局部药效、降低炎症反应及延长作用时间方面具有显著优势，为膀胱局部递送提供了一种高效、安全的新策略。

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a urological disorder characterized by bladder hypersensitivity, urinary frequency, urgency, and chronic pelvic pain. Current treatment options include oral medications, bladder instillation, and surgical interventions. However, due to the unique anatomical structure of the urinary system, traditional oral or intravenous administration is often limited by factors such as the first-pass effect, high systemic exposure, and insufficient drug concentration at the target tissue, resulting in unsatisfactory therapeutic outcomes. In contrast, intravesical drug delivery can enhance local drug concentrations, compensating for the shortcomings of systemic administration. However, it still faces several challenges, including short residence time, low bioavailability, and poor patient compliance, which restrict its overall efficacy. In recent years, local targeted drug delivery systems have gained significant attention in research. Among these, phospholipid-based excipients have shown great promise due to their excellent biocompatibility, cell membrane-like structure, and solubilizing properties, making them widely used to improve the transmembrane permeability and tissue retention of poorly soluble drugs. However, the complex physiological environment of the bladder (such as urinary flushing and mucosal barriers) poses greater demands on the stability and adhesion of nanoparticle formulations. This calls for the need for functional modifications to optimize the performance of the drug delivery system and enhance its therapeutic potential.

Forsythin, one of the main active ingredients of the traditional Chinese medicine Forsythia suspensa, possesses anti-inflammatory, antiviral, and antioxidant properties. It can reduce the expression of pro-inflammatory cytokines such as IL-6 and TNF-α, while scavenging reactive oxygen species (ROS) to alleviate oxidative stress damage. However, due to its poor water solubility and low oral bioavailability, the clinical application of forsythin in the treatment of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is limited. In this study, we employed nanotechnology-based drug delivery systems to construct Forsythin-phospholipid complexes (FPC) and solid lipid nanoparticles (FOS and FPS), and further developed chitosan-modified phospholipid complexes (CTS-FPC) to enhance the drug's local retention and sustained release properties, providing a new therapeutic strategy for IC/BPS.

First, we compared two mainstream modeling strategies: bladder instillation of lipopolysaccharide (LPS) combined with protamine sulfate (PS) and intraperitoneal injection of cyclophosphamide (CYP). Through histological examination, inflammatory factor analysis, and tissue evaluations, we identified the most stable and reliable modeling approach. The results demonstrated that the CYP-induced model could effectively simulate acute, subacute, and chronic inflammatory phenotypes in a gradient manner, offering a reliable platform for subsequent pharmacodynamic evaluations.

On this basis, potential therapeutic agents were screened, including phosphodiesterase-4 (PDE-4) inhibitors (dm0420, roflumilast) and chondroitin sulfate analogs (CS, PACS), for their effects on bladder barrier repair. The results demonstrated that PDE-4 inhibitors effectively improved barrier integrity, while chondroitin sulfate analogs exhibited protective effects in therapeutic administration but had limited preventive efficacy. Subsequently, FPC, FOS and FPS were developed and characterized using Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), particle size, and Zeta potential analysis. In vitro release studies showed that FPC significantly enhanced the water solubility and transmembrane permeability of forsythin, with a 6-hour cumulative release rate of 82.97%, compared to free forsythin. FPS further optimized drug release in the bladder, demonstrating a sustained-release profile, with a 24-hour cumulative release rate reduced to 65.38%, effectively prolonging the drug's action duration. Pharmacodynamic studies revealed that FPS significantly reduced IL-6 and TNF-α expression in bladder tissues and showed significant differences in pain scores, indicating strong anti-inflammatory and analgesic effects. Intravesical delivery experiments further confirmed that in rats, the bladder tissue AUC of FPS was 6.9 times higher than that of free forsythin, while T_₁/₂ was extended from 0.54 h to 8.27 h, enhancing both bioavailability and sustained drug release.

To further prolong bladder retention, chitosan (CTS), a cationic polysaccharide, was introduced to modify FPC, forming the CTS-FPC nanodelivery system. Characterization results showed a slight increase in particle size and a shift in surface charge from negative to positive following CTS modification. In the chronic IC model, CTS-FPC demonstrated superior anti-inflammatory effects, significantly reducing Evans Blue leakage (P<0.0001), bladder edema, and inflammation scores (P<0.001), while markedly decreasing IL-6 and TNF-α expression levels and alleviating mucosal edema and spontaneous pain. Small animal in vivo imaging and histological distribution studies further confirmed that CTS-FPC remained in bladder tissues for up to 96 hours, exhibiting excellent mucoadhesion and sustained-release properties.

In summary, this study successfully developed a nanodelivery system based on Forsythin and optimized its sustained release properties and anti-inflammatory efficacy. FPC enhanced the bioavailability of Forsythin, while FPS extended the drug's action time through a sustained release mechanism. Furthermore, CTS-FP improved the bladder retention ability, achieving the "long-lasting - high-efficiency" therapeutic goal. The results indicate that this novel delivery system offers significant advantages in improving the local efficacy, reducing inflammation, and prolonging the drug’s action time for IC/BPS treatment. It provides a new, efficient, and safe strategy for intravesical drug delivery.