Against a backdrop of global antibiotic resistance and increasing awareness of the importance of the human microbiota, there has been resurgent interest in the potential use of bacteriophages for therapeutic purposes, known as phage therapy. A number of phage therapy phase I and II clinical trials have concluded, and shown phages don't present significant adverse safety concerns. These clinical trials used simple phage suspensions without any formulation and phage stability was of secondary concern. Phages have a limited stability in solution, and undergo a significant drop in phage titre during processing and storage which is unacceptable if phages are to become regulated pharmaceuticals, where stable dosage and well defined pharmacokinetics and pharmacodynamics are de rigueur. Animal studies have shown that the efficacy of phage therapy outcomes depend on the phage concentration (i.e. the dose) delivered at the site of infection, and their ability to target and kill bacteria, arresting bacterial growth and clearing the infection. In addition, in vitro and animal studies have shown the importance of using phage cocktails rather than single phage preparations to achieve better therapy outcomes. The in vivo reduction of phage concentration due to interactions with host antibodies or other clearance mechanisms may necessitate repeated dosing of phages, or sustained release approaches. Modelling of phage-bacterium population dynamics reinforces these points. Surprisingly little attention has been devoted to the effect of formulation on phage therapy outcomes, given the need for phage cocktails, where each phage within a cocktail may require significantly different formulation to retain a high enough infective dose.

This review firstly looks at the clinical needs and challenges (informed through a review of key animal studies evaluating phage therapy) associated with treatment of acute and chronic infections and the drivers for phage encapsulation. An important driver for formulation and encapsulation is shelf life and storage of phage to ensure reproducible dosages. Other drivers include formulation of phage for encapsulation in micro- and nanoparticles for effective delivery, encapsulation in stimuli responsive systems for triggered controlled or sustained release at the targeted site of infection. Encapsulation of phage (e.g. in liposomes) may also be used to increase the circulation time of phage for treating systemic infections, for prophylactic treatment or to treat intracellular infections. We then proceed to document approaches used in the published literature on the formulation and stabilisation of phage for storage and encapsulation of bacteriophage in micro- and nanostructured materials using freeze drying (lyophilization), spray drying, in emulsions e.g. ointments, polymeric microparticles, nanoparticles and liposomes. As phage therapy moves forward towards Phase III clinical trials, the review concludes by looking at promising new approaches for micro- and nanoencapsulation of phages and how these may address gaps in the field.

在全球抗生素抗性和对人类微生物群重要性的认识日益提高的背景下，人们对将噬菌体用于治疗目的（称为噬菌体疗法）的潜在用途产生了浓​​厚的兴趣。I期和II期噬菌体治疗的许多临床试验已经结束，表明噬菌体并未带来重大的不良安全隐患。这些临床试验使用没有任何制剂的简单噬菌体悬浮液，并且噬菌体的稳定性是次要关注的问题。噬菌体在溶液中具有有限的稳定性，以及处理和存储这是不可接受的，如果噬菌体是成为调节药物，其中稳定剂量和良好定义的药代动力学和药效学是期间经历在噬菌体滴度显著下降平常的。动物研究表明，噬菌体治疗结局的有效性取决于感染部位递送的噬菌体浓度（即剂量），以及它们靶向和杀死细菌，阻止细菌生长并清除感染的能力。此外，体外和动物研究表明，使用噬菌体鸡尾酒而不是单一噬菌体制剂来获得更好的治疗效果非常重要。由于与宿主抗体或其他清除机制的相互作用而导致体内噬菌体浓度的降低可能需要对噬菌体进行重复给药或采用持续释放的方法。噬菌体细菌种群动态的模型强化了这些观点。令人惊讶的是，由于需要噬菌体鸡尾酒，因此很少有人关注制剂对噬菌体治疗结果的影响，

这篇综述首先着眼于与急，慢性感染的治疗和噬菌体包囊驱动因素相关的临床需求和挑战（通过对评估噬菌体治疗的关键动物研究的综述来告知）。配制和封装的重要驱动因素是保质期和噬菌体的储存，以确保可重复的剂量。其他驱动因素包括噬菌体制剂，用于封装在微粒和纳米颗粒中以进行有效传递，封装在刺激响应系统中，以在感染的目标部位触发受控或持续释放。噬菌体的包囊（例如在脂质体中）也可用于增加噬菌体的循环时间以治疗全身性感染，预防性治疗或治疗细胞内感染。然后，我们继续记录已发表文献中使用的冷冻干燥（冻干），喷雾干燥，乳状液（如软膏，聚合物微粒，纳米颗粒和纳米颗粒）中用于配制和稳定噬菌体的方法，以用于噬菌体在微结构和纳米结构材料中的存储和封装。脂质体。随着噬菌体治疗朝着III期临床试验的方向发展，本综述以寻找有前景的噬菌体微囊和纳米囊封新方法以及这些方法如何解决该领域的空白作为总结。