Non-adherence to medication is a major challenge in healthcare that results in worsened treatment outcomes for patients. Reducing the frequency of required administrations could improve adherence but is challenging for topical drug delivery due to the generally short residence time of topical formulations on the skin. In this study, we sought to determine the feasibility of developing a microbiome-based, long-acting, topical delivery platform using Bacillus subtilis for drug production and delivery on the skin, which was assessed using green fluorescent protein as a model heterologous protein for delivery. We developed a computational model of bacteria population dynamics on the skin and used its qualitative predictions to guide experimental design choices. Using an ex vivo pig skin model and a human skin tissue culture model, we saw persistence of delivered bacteria for multiple days and observed little evidence of cytotoxicity to human keratinocyte cells in vitro. Finally, using an in vivo mouse model, we found that the delivered bacteria persisted on the skin for at least 1 day during every-other-day application and did not appear to present safety concerns. Taken together, our results support the feasibility of using engineered B. subtilis for topical drug delivery.

中文翻译：

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工程枯草芽孢杆菌用作基于微生物组的局部给药平台的可行性

不坚持用药是医疗保健领域的一个重大挑战，会导致患者的治疗结果恶化。减少所需给药的频率可以提高依从性，但由于局部制剂在皮肤上的停留时间通常较短，因此对于局部药物递送来说具有挑战性。在本研究中，我们试图确定使用枯草芽孢杆菌开发基于微生物组的长效局部递送平台用于药物生产和皮肤递送的可行性，并使用绿色荧光蛋白作为模型异源蛋白进行评估。我们开发了皮肤上细菌种群动态的计算模型，并利用其定性预测来指导实验设计选择。使用离体猪皮肤模型和人皮肤组织培养模型，我们观察到递送的细菌可以持续多天，并且在体外观察到几乎没有对人角质形成细胞具有细胞毒性的证据。最后，使用体内小鼠模型，我们发现每隔一天使用一次，所输送的细菌在皮肤上持续存在至少 1 天，并且似乎不存在安全问题。总而言之，我们的结果支持使用工程枯草芽孢杆菌进行局部药物递送的可行性。