Decorated bacteria and the application in drug delivery

Abstract

The use of living bacteria either as therapeutic agents or drug carriers has shown great potential in treating a multitude of intractable diseases. However, cells are often fragile to unfriendly environmental stressors and limited by inadequately therapeutic responses, leading to unwanted cell death and a decline in treatment efficacy. Surface decoration of bacteria has emerged as a simple yet useful strategy that not only confers bacteria with extra capacity to resist environmental threats but also endows them with exogenous characteristics that are neither inherent nor naturally achievable. In this review, we systematically introduce the advancements of physicochemical and biological technologies for surface modification of bacteria, especially the single-cell surface decoration strategies of individual bacteria. We highlight the recent progress on surface decoration that aims to improve the bioavailability and efficacy of therapeutic bacterial agents and also to achieve enhanced and targeted delivery of conventional drugs. The promises along with challenges of surface-decorated bacteria as drug delivery systems for applications in cancer therapy, intestinal disease treatment, bioimaging, and diagnosis are further discussed with respect to future clinical translation. This review offers an overview of the advances of decorated bacteria for drug delivery applications and would contribute to the development of the next generation of advanced bacterial-based therapies.

Introduction

The human body is inhabited by trillions of bacteria, which are microbes found on the skin, in the open cavities of healthy humans, such as the oral cavity, gastrointestinal (GI) tract and reproductive tract, and even in patients’ tumors [1], [2]. An indispensable symbiotic relationship has formed between bacteria and hosts over the eon of coevolution. Bacteria participate in some complicated physiological activities, including immune regulation, digestion of food, absorption and metabolism of nutrients and drugs, prevention of pathogen colonization, and intestinal barrier function [3], [4]. It has been established that bacteria are closely related to the pathogenesis and progression of a range of diseases, for example, diabetes, obesity, metabolic syndrome, psychiatric disorders, autoimmune diseases, and cancer [5], [6], [7]. Furthermore, bacteria possess fascinating peculiarities such as inherent motility, preferential colonization in tumors, and immunoregulation [8], [9]. These characteristics and functionalities of bacteria motivate their application as emerging therapeutic candidates for treating disease and maintaining homeostasis and health.

With the development of genetic engineering and synthetic biology technology, bacteria-mediated therapy has rapidly moved forward in biomedical field in the past decades [10], [11]. Bacteria can serve as therapeutic agents to treat diseases by exerting their innate functions, such as activating immunity and secreting bacteriocins. On the other hand, bacteria are widely used as carriers to deliver classical clinical drugs to hypoxic lesions, increasing drug availability at disease sites, and further improving therapeutic efficacy [12]. However, significant challenges remain to be addressed for bacterial therapy. Bacteria tend to be delicate to adverse environmental pressures and are restricted by insufficiently therapeutic responses, leading to undesired cell death and unsatisfactory therapeutic effect. For instance, oral administration of probiotics has been applied to treat inflammatory bowel disease (IBD). The GI environment is complicated and the associated substances are in a state of constant agitation. There are pepsin and fairly low pH in the stomach and digestive enzymes and bile acids in the intestine. The hostile GI circumstance has a great negative impact on the activity of probiotics, which causes deficient delivery and colonization in the intestinal tract as well as drastic reductions in bioavailability and treatment efficacy [13]. In addition, clinical application of bacterial therapy is limited by bacterial virulence derived from immunogenicity and invasiveness related to bacterial surface and excretions, which may induce severe adverse effects [14]. There is an urgent need for innovative strategies to solve these difficulties.

Bulk encapsulation of living probiotics into a micron-scale gel matrix or enteric capsule has been commonly used for protecting probiotic cells. Despite certain advances in increasing probiotic viability, the inability to control leakage [15] and bead size [16] and low in vivo efficacy have limited the clinical translation of these microencapsulation approaches [17]. Recently, single-cell encapsulation of individual probiotic cells via surface decoration with nanocoating has emerged as a viable alternative to address these challenges [18]. Surface decoration is an important approach to achieve improvement and innovation of material properties, confer materials with new functions and features, and ultimately determine the overall performance [19], [20]. Surface modification of bacteria, especially single-cell decoration, is an interdisciplinary research field that integrates the disciplines of biology, chemistry, engineering, and materials science [21]. Inherent antigens, adhesion factors, and flagella on the surface of bacteria are key elements for their communication and interaction with the surroundings and play vital roles in their biological functionalities. A variety of chemical and biological approaches have been developed for the surface decoration of individual bacteria in the past few decades. There are three main pursuits regarding the development of different strategies for bacterial surface decoration: 1) camouflaging bacteria to reduce their immunogenicity and pathogenicity and to improve the safety of bacterial therapy without affecting their viability and proliferation capability; 2) protecting bacteria and strengthening their resistance against environmental threats to enhance the bacterial bioavailability or drug availability in the disease sites; 3) endowing bacteria with exogenous functions that are neither inherent nor naturally achievable to effectively and precisely control bacterial activity and biological behavior for increased treatment efficacy. Bacterial surface decoration strategies have innovatively addressed the shortcomings of current bacterial therapy and opened a new window for the development of bacteria-mediated therapies. In this review, we provide a systematic summary on the current physicochemical and biological methods related to surface decoration of individual bacteria and introduce the applications of surface-decorated bacteria as engineered drug delivery systems (Fig. 1).