State Key Laboratory of Silkworm Genome Biology, Chongqing Engineering and Technology Research Center for Novel Silk Materials, Biological Science Research Center, Southwest University, Chongqing, 400715, PR China.
Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA.
Acta Biomater. 2022 May;144:81-95. doi: 10.1016/j.actbio.2022.03.012. Epub 2022 Mar 12.
Ulcerative colitis (UC) is one type of inflammatory bowel disease (IBD) and lactoferrin (LF) is a promising protein drug to treat UC. However, targeted LF delivery to optimize bioavailability, targeting and effectiveness remains a challenge. Here, we report an effective strategy to fabricate silk sericin nanospheres systems for the delivery of recombinant human lactoferrin (SS-NS-rhLF). The system is based on the use of optimized transgenic silkworms to generate genetically engineered silk fibers (rhLF-silks). The rhLF silks were used for fabricating SS-NS-rhLF by ethanol precipitation. The SS-NS-rhLF were stable with a spherical morphology with an average diameter of 123 nm. The negatively charged sericins in a pH ≥ 5.5 environment achieved specific targeting of the SS-NS-rhLF to positively charged colonic sites. The SS-NS-rhLF achieved efficient uptake by cells in the inflamed colon of mice when compared to free lactoferrin in solution (SOL-rhLF). Furthermore, oral administration of the SS-NS-rhLF with low dose of rhLF significantly relived symptoms of UC in mice and achieved comparable therapeutic effect to the high dose of SOL-rhLF by supporting the reformation of cell structure and length of colon tissue, reducing the release of inflammatory factors, inhibiting the activation of the NF-κB inflammatory pathway, and maintaining a stable intestinal microbial population in mice. These results showed that the SS-NS-rhLF is a promising system for colitis treatment. STATEMENT OF SIGNIFICANCE: Targeting and effective delivery of multiple biological functional protein human lactoferrin (rhLF) is a promising strategy to treat ulcerative colitis in the clinic. Here, rhLF-transgenic silk cocoons were used to fabricate a rhLF-sericin nanosphere delivery system (SS-NS-rhLF). The fabricated SS-NS-rhLF showed identical spherical morphology, stable structure, sustainable rhLF release, efficient cell uptake and negative charge in an environment of pH above 5.5, thus realized the specific targeting to the positively charged colonic sites to treat UC mice through oral administration. The therapeutic effect of SS-NS-rhLF with a low rhLF dose in the UC mice was comparable to the high dose of free rhLF treatment in solution form, suggesting that the SS-NS-rhLF is a promising system for colitis treatment.
溃疡性结肠炎（UC）是一种炎症性肠病（IBD），乳铁蛋白（LF）是一种有前途的治疗 UC 的蛋白质药物。然而，将 LF 靶向递送至优化生物利用度、靶向和效果仍然是一个挑战。在这里，我们报告了一种有效的策略，用于制造丝胶纳米球系统以递送重组人乳铁蛋白（SS-NS-rhLF）。该系统基于使用优化的转基因蚕来产生基因工程丝纤维（rhLF-丝绸）。rhLF 丝绸用于通过乙醇沉淀来制备 SS-NS-rhLF。在 pH 值≥5.5 的环境中带负电荷的丝胶实现了 SS-NS-rhLF 对带正电荷的结肠部位的特异性靶向。与溶液中的游离乳铁蛋白（SOL-rhLF）相比，SS-NS-rhLF 能够有效地被炎症结肠中的细胞摄取。此外，与 SOL-rhLF 高剂量相比，低剂量 rhLF 的 SS-NS-rhLF 口服给药可显著缓解 UC 小鼠的症状，并通过支持结肠组织结构和长度的重构、减少炎症因子的释放、抑制 NF-κB 炎症途径的激活以及维持肠道微生物种群的稳定来实现相当的治疗效果。这些结果表明，SS-NS-rhLF 是一种有前途的结肠炎治疗系统。
