활성 산소 ROS, RNS, RSS, RCS 내인성, 외인성 항산화제.. 탐구!!

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Oxidative Stress and Antioxidant Nanotherapeutic Approaches for Inflammatory Bowel Disease

by 

Ping Liu

 1,

Yixuan Li

 1,

Ran Wang

 1,

Fazheng Ren

 1 and

Xiaoyu Wang

 1,2,*

1

Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China

2

Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China

*

Author to whom correspondence should be addressed.

Biomedicines 2022, 10(1), 85; https://doi.org/10.3390/biomedicines10010085

Submission received: 3 December 2021 / Revised: 29 December 2021 / Accepted: 30 December 2021 / Published: 31 December 2021

(This article belongs to the Special Issue Oxidative Stress and Inflammation: From Mechanisms to Therapeutic Approaches 3.0)

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Abstract

Oxidative stress, caused by the accumulation of reactive species, is associated with the initiation and progress of inflammatory bowel disease (IBD). The investigation of antioxidants to target overexpressed reactive species and modulate oxidant stress pathways becomes an important therapeutic option. Nowadays, antioxidative nanotechnology has emerged as a novel strategy. The nanocarriers have shown many advantages in comparison with conventional antioxidants, owing to their on-site accumulation, stability of antioxidants, and most importantly, intrinsic multiple reactive species scavenging or catalyzing properties. This review concludes an up-to-date summary of IBD nanomedicines according to the classification of the delivered antioxidants. Moreover, the concerns and future perspectives in this study field are also discussed.

반응성 종의 축적으로 인한 산화 스트레스는 

염증성 장 질환(IBD)의 시작 및 진행과 관련이 있습니다. 

과발현된 반응성 종을 표적으로 삼고 

산화 스트레스 경로를 조절하는 항산화제를 연구하는 것이 

중요한 치료 옵션이 되고 있습니다. 

최근에는 항산화 나노기술이 새로운 전략으로 부상하고 있습니다. 

나노 담체는 현장 축적, 항산화제의 안정성, 그리고 무엇보다도 내재된 다중 반응성 종 제거 또는 촉매 특성으로 인해 기존 항산화제에 비해 많은 이점을 보여주었습니다. 이 리뷰는 전달되는 항산화제의 분류에 따른 IBD 나노 의약품의 최신 요약으로 마무리합니다. 또한 이 연구 분야의 우려 사항과 향후 전망에 대해서도 논의합니다.

Keywords: 

oxidative stress; reactive species; inflammatory bowel disease (IBD); antioxidant pathways; nano-delivery systems

1. Introduction

Oxidative stress is the imbalance between the generation of reactive species and the ability to defend against oxidative damage that may lead to the disruption of biological systems. Both oxidation and reduction processes can be generated from endogenous and exogenous sources [1]. It is a cause of a wide range of diseases, including chronic obstructive pulmonary disease, cardiovascular diseases, neurodegenerative diseases, chronic kidney disease, and cancer as well as IBD [2,3]. In intestinal tissues, the response of oxidative stress and inflammation, in turn, involves multiple cell types such as intestinal epithelial cells, innate immune cells as well as adaptive immune cells [4,5]. Meanwhile, in the immune cells, two key transcription factors, Nuclear factor kappaB (NF-κB) and NF-E2p45-related factor 2 (Nrf2), are crucial transcription pathways that regulate a broad range of physiological functions and related genes [3,6,7,8,9]. The products are suggested as either therapeutic targets or biomarkers.

In comparison with the traditional treatment for IBD, nano-drug delivery systems are capable of precisely targeting the inflammatory site, instead of the entire gut. It is beneficial for maintaining long-term remission to cure chronic diseases. Owing to their small size and versatile physiochemical properties, nanomedicines are of particular interest among the accumulation in the inflamed site and response approaches in IBD. Thus, they can effectively enhance the stability of antioxidants and penetrate the antioxidants into inflammatory sites [10,11,12]. In this review, we will focus on the up-to-date antioxidative nanomedicines that have emerged, mainly within the last five years, concerning the management of IBD by oral administration. Depending on the delivery compounds, the antioxidant nanosystems are classified into four catalogs: protein and peptide nanocarriers, nucleic acid nanocarriers, small antioxidant compound nanocarriers, and nanozymes. The last part deals with a general conclusion of concerns in the study and potential research ideas.

1. 소개

산화 스트레스는

반응성 종의 생성과 생물학적 시스템의 파괴로 이어질 수 있는

산화적 손상을 방어하는 능력 사이의 불균형을 말합니다.

Oxidative stress is

the imbalance between

the generation of reactive species and the ability to defend against oxidative damage

that may lead to the disruption of biological systems.

산화 및 환원 과정은

모두 내인성 및 외인성 소스에서 생성될 수 있습니다[1].

이는

만성 폐쇄성 폐질환, 심혈관 질환, 신경 퇴행성 질환, 만성 신장 질환 및

암뿐만 아니라 IBD를 포함한 광범위한 질병의 원인입니다 [2,3].

장 조직에서

산화 스트레스와 염증의 반응은

장 상피 세포, 선천성 면역 세포 및 적응 면역 세포와 같은

여러 유형의 세포를 차례로 포함합니다 [4,5].

한편,

면역 세포에서

핵 인자 카파B(NF-κB)와 NF-E2p45 관련 인자 2(Nrf2)는

광범위한 생리적 기능과 관련 유전자를 조절하는 중요한 전사 경로입니다[3,6,7,8,9].

이들은

치료 표적 또는 바이오마커로 제시되고 있습니다.

Meanwhile, in the immune cells,

two key transcription factors,

Nuclear factor kappaB (NF-κB) andNF-E2p45-related factor 2 (Nrf2),

are crucial transcription pathways that regulate a broad range of physiological functions and related genes [3,6,7,8,9].

The products are suggested as either therapeutic targets or biomarkers.

기존의 IBD 치료법과 비교하여 나노 약물 전달 시스템은 장 전체가 아닌 염증 부위를 정밀하게 표적으로 삼을 수 있습니다. 만성 질환을 치료하기 위해 장기적인 관해 상태를 유지하는 데 유리합니다. 작은 크기와 다양한 생화학적 특성으로 인해 나노 의약품은 염증 부위 축적과 IBD의 대응 접근법 중 특히 관심을 받고 있습니다. 따라서 항산화제의 안정성을 효과적으로 향상시키고 항산화제를 염증 부위에 침투시킬 수 있습니다[10,11,12]. 이 리뷰에서는 경구 투여를 통한 IBD 관리와 관련하여 주로 지난 5년 이내에 등장한 최신 항산화 나노 의약품에 초점을 맞출 것입니다. 항산화 나노 시스템은 전달 화합물에 따라 단백질 및 펩타이드 나노 담체, 핵산 나노 담체, 소형 항산화 화합물 나노 담체, 나노 효소의 네 가지로 분류됩니다. 마지막 부분에서는 연구의 전반적인 결론과 잠재적인 연구 아이디어를 다룹니다.

2. The Reactive Species and Oxidative Stress

The oxidation-reduction reaction is related to all fundamental biological processes [2,3]. The reactive spices are produced by several oxidation processes and can be partially neutralized by the antioxidant defense. In addition to reactive oxygen species (ROS) (e.g., superoxide, peroxides, hydroxyl radical, α-oxygen, and singlet oxygen), other types of reactive spices also have remarkable impacts on cellular redox processes, including reactive nitrogen species (RNS) (e.g., nitric oxide and nitrogen dioxide), reactive sulfur species (RSS) (e.g., persulfides, polysulfide, and thiosulfate), and reactive carbonyl species (RCS) (protein aldehydes and protein carbonyls) [1]. The reactive species are generated from both endogenous and exogenous sources. Reactive species produced primarily rely on endogenous enzymatic reactions [2].

The metabolism processes, mitochondrial respiratory chain, prostaglandin synthesis, and phagocytosis are all involved. For instance, myeloperoxidase (MPO), nicotinamide adenine dinucleotide phosphate (NADPH), oxidase, angiotensin II, and lipoxygenase are noticeable [13]. The exogenous sources of reactive species production can occur as a result of exposure to environmental pollutions, heavy metals (e.g., cadmium [Cd], mercury [Hg], lead [Pb], and arsenic [As]), certain drugs (e.g., cyclosporine, tacrolimus, gentamycin, and bleomycin), organic solvents, alcohol, and radiations [14]. Correspondingly, the antioxidant defense from free reactive species’ toxicity can be divided into endogenous and exogenous pathways [2]. Endogenous antioxidants include enzymes, for instance, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GSH-Px), thioredoxin (Trx), and peroxiredoxins (Prxs), as well as the low-molecular-mass antioxidants, such as bilirubin, β-carotene, Vitamin E, albumin, and uric acid in plasma. Exogenous antioxidants refer to Vitamin C, Vitamin E, polyphenols, flavonoids, metals (e.g., selenium [Se], copper [Cu], zinc [Zn]), metal oxides, and drugs [1,15,16,17]. Some compounds act as scavengers of reactive species, whereas the others have no such effect directly. The metals or metal oxides are referred to as antioxidant minerals because they defend against oxidative stress by chelation of transition metals and preventing them from catalyzing the production of endogenous reactive species. For instance, Se and Zn have no direct antioxidant function but are necessary for the activity of antioxidant enzymes [18,19,20]. Notably, as has been commonly acknowledged, in comparison to the individual antioxidants, the mixtures exhibit synergistic effects [21,22,23].

Oxidative stress takes place owing to the imbalance between reactive species and antioxidants. It leads to a disorder of redox signaling and damage to biomolecules [24]. The accumulated reactive species, which originate from either endogenous or exogenous sources, cause oxidative modification of the cellular macromolecules: nucleic acids, proteins, lipids, and carbohydrates [2] (Figure 1). The oxidative macromolecules in turn can be employed as biomarkers to quantify oxidative stress [25]. A considerable number of studies demonstrate that oxidative stress has existed in all the aerobic cells and can be responsible, with different degrees of importance, for the onset and/or the progression of common age-related diseases (e.g., cardiovascular disease, cancer, and diabetes) or inflammatory diseases (e.g., metabolic disorders, autoimmune disorders, and IBD) [2,15].

2. 반응성 종과 산화 스트레스

산화-환원 반응은

모든 근본적인 생물학적 과정과 관련이 있습니다 [2,3].

반응성 물질은

여러 산화 과정에 의해 생성되며

항산화 방어에 의해 부분적으로 중화될 수 있습니다.

활성 산소 종(ROS)(예: 슈퍼옥사이드, 과산화물, 하이드록실 라디칼, α 산소 및 단일 산소) 외에도

다른 유형의 반응성 물질인

반응성 질소 종(RNS)을 포함하여

세포 산화 환원 과정에 현저한 영향을 미칩니다, 산화질소 및 이산화질소), 반응성 황종(RSS)(예: 퍼설파이드, 폴리설파이드, 티오설페이트), 반응성 카르보닐 종(RCS)(단백질 알데히드 및 단백질 카르보닐)[1] 등이 있습니다.

In addition to reactive oxygen species (ROS)

(e.g., superoxide, peroxides, hydroxyl radical, α-oxygen, and singlet oxygen),

other types of reactive spices also have remarkable impacts on cellular redox processes,

including reactive nitrogen species (RNS) (e.g., nitric oxide and nitrogen dioxide),

reactive sulfur species (RSS) (e.g., persulfides, polysulfide, and thiosulfate), and

reactive carbonyl species (RCS) (protein aldehydes and protein carbonyls) [1]

반응성 종은

내인성 및 외인성 소스 모두에서 생성됩니다.

반응성 종은

주로 내인성 효소 반응에 의존하여 생성됩니다[2].

대사 과정,

미토콘드리아 호흡 사슬,

프로스타글란딘 합성 및

식세포 작용이 모두 관여합니다.

예를 들어,

미엘로퍼옥시다제(MPO),

니코틴아마이드 아데닌 디뉴클레오티드 인산염(NADPH),

옥시다제,

안지오텐신 II 및 리폭시게나제가

눈에 띕니다 [13].

반응성 종 생성의 외인성 원인은

환경 오염, 중금속(예: 카드뮴[Cd], 수은[Hg], 납[Pb], 비소[As]),

특정 약물(예: 사이클로스포린, 타크로리무스, 젠타마이신, 블레오마이신),

유기 용매,

알코올 및 방사선에 노출될 경우 발생할 수 있습니다[14].

이에 따라

활성산소종의 독성에 대한 항산화 방어는

내인성 및 외인성 경로로 나눌 수 있습니다[2].

내인성 항산화제는

슈퍼옥사이드 디스뮤타제(SOD),

카탈라아제(CAT),

글루타치온 퍼옥시다제(GSH-Px),

티오레독신(Trx),

퍼옥시레독신(Prx) 등의 효소와

혈장 내 빌리루빈,

β-카로틴,

비타민 E,

알부민,

요산 등의 저 분자량 항산화제를 포함합니다.

외인성 항산화제는

비타민 C, 비타민 E, 폴리페놀, 플라보노이드,

금속(예: 셀레늄[Se], 구리[Cu], 아연[Zn]),

금속 산화물 및 약물을 말합니다[1,15,16,17].

일부 화합물은

반응성 종의 제거제 역할을 하는 반면,

다른 화합물은 직접적인 영향을 미치지 않습니다.

금속 또는 금속 산화물은

전이 금속의 킬레이트화를 통해

산화 스트레스를 방어하고

내인성 반응성 종의 생성을 촉매하지 못하도록 하기 때문에

항산화 미네랄이라고 불립니다.

예를 들어,

Se와 아연은 직접적인 항산화 기능은 없지만

항산화 효소의 활성에 필요합니다[18,19,20].

특히, 일반적으로 알려진 바와 같이 개별 항산화제와 비교할 때 혼합물은 시너지 효과를 나타냅니다 [21,22,23].

산화 스트레스는

반응성 종과 항산화제 간의 불균형으로 인해 발생합니다.

산화 환원 신호의 장애와 생체 분자의 손상으로 이어집니다 [24].

내인성 또는 외인성 소스에서 비롯된 축적된 반응성 종은

핵산, 단백질, 지질, 탄수화물과 같은

세포 거대 분자의 산화적 변형을 일으킵니다[2](그림 1).

이러한 산화성 거대 분자는 산화 스트레스를 정량화하기 위한 바이오마커로 사용될 수 있습니다[25]. 상당수의 연구에 따르면 산화 스트레스는 모든 호기성 세포에 존재하며, 중요도는 다르지만 일반적인 노화 관련 질환(예: 심혈관 질환, 암, 당뇨병) 또는 염증성 질환(예: 대사 장애, 자가 면역 장애, IBD)의 발병 및 진행에 책임이 있을 수 있습니다[2,15].

Figure 1. The imbalance between the generation of reactive species and the antioxidant defense system results in oxidative stress and further damage to cellular macromolecules.

반응성 종의 생성과 항산화 방어 시스템 사이의 불균형은 

산화 스트레스와 

세포 거대 분자에 대한 추가 손상을 초래합니다.

ROS—reactive oxygen species;

RNS—reactive nitrogen species;

RSS—reactive sulfur species;

RCS—reactive carbonyl species;

VC—ascorbic acid;

VE—tocopherol.

Created by BioRender.com.

3. Oxidative Stress and IBD

IBD is idiopathic chronic and relapsing inflammatory disorder of the gut, which comprises ulcerative colitis and Crohn’s disease [5]. Both are caused by an overactive immune response to gut microbiota in genetically vulnerable individuals [26]. Ulcerative colitis is limited to the colon, whereas Crohn’s disease is regarded as inflammation in the whole gastrointestinal tract in a non-continuous fashion [5,27]. The precise etiology of IBD has been studied for decades and remains unclear. The interaction of various factors, including genetic factors, the immune system, and environmental factors interrupt the homeostasis of the gut (e.g., oxidative stress), leading to inflammatory responses of the intestinal tissue [4,28]. Numerous research pieces of evidence suggest that IBD is associated with the increased production of reactive species. To be exact, multiple studies in colitis animal models proved an augmented formation of reactive species, including superoxide, peroxynitrite, hypochlorous acid, and hydrogen peroxide; meanwhile, the levels of endogenous reactive species-related compounds in colonic tissue, such as glutathione and Cu/ZnSOD, are decreased [28]. Studies using genetically modified animal models to select the appropriate modifications of antioxidant enzymes were the most convincing proof for the cause-and-effect relationship between oxidative stress and IBD [29]. For instance, transgenic overexpressed Cu/ZnSOD significantly attenuated DDS-induced colitis. Depletion of GPx1 and GPx2 or additional glutathione biosynthesis inhibitors (e.g., buthionine sulfoximine) caused the generation of colitis in mice [28,30].

Oxidative stress not only directly damages the intestinal epithelial cells but also causes dysregulated pro-inflammatory reactive species-sensitive pathways in immune cells [7]. The NF-κB signaling and Nrf2 signaling pathways are two key transcription pathways that regulate a broad range of biological functions to respond to oxidative stress and inflammation [9]. The multi-subunit transcription factor NF-κB serves as a pivotal mediator of multiple aspects of both innate and adaptive immune systems. It controls the expression‎ of a series of pro-inflammatory genes, encoding cytokines and chemokines. Additionally, NF-κB directs the survival, migration, and differentiation of immune cells. While reactive species can react with proteins, lipids, polysaccharides, and nucleic acids of NF-κB pathways, this pathway is sensitive to the molecules [6]. In one classic study, NF-κB responded to micromolar concentrations of H2O2 and this activation was reversed by treatment with antioxidant N-acetyl cysteine (NAC) [31]. Strong evidence indicates that NF-κB is associated with the pathogenesis of IBD patients. The irregulation of NF-κB precursors, NF-κB, the NF-κB stimulating immune receptors (e.g., NOD2), and the down-regulation gens (e.g., interleukins (IL)-12, IL-23) has been found in inflamed colonic tissue of IBD patients [30]. On the other hand, Nrf2 belongs to another family of transcription factors, being capable of inducing a set of antioxidants and detoxication enzymes [3]. The factor-induced transcription of antioxidant proteins is able to protect against the accumulation of overproduced reactive species. The most studied Nrf2-related proteins or protein subunits are NAD(P)H, heme oxygenase-1 (HO-1), dehydrogenase quinone 1 (NQO1), catalytic subunit (GCLC), and the γ-glutamyl cysteine ligase modulatory subunit (GCLM). It is also related to pro-inflammatory cytokines like IL-6, IL-1β, and IL-17, extracellular matrix degradation proteins including matrix metalloproteinase (MMPs), and autophagy modulations [32,33]. Additionally, the cellular level of Nrf2 is strictly regulated. For example, the binding with Kelch-like ECH-associated protein1 (Keap1)-Cullin2-Rbx1 complex causes Nrf2 ubiquitination. The stability of the Nrf2/Keap1 complex is sensitive to oxidant stress, while Keap1 protein contains 27 cysteine residues, which can be modified by reactive species [34]. Interestingly, the complex interplay of NF-κB and Nrf2 pathways under conditions of oxidative stress could cause the fine-tuning of dynamic responses by either transcriptional or post-transcriptional mechanisms. For instance, NF-κB directly modulates the Nrf2 transcription and activity, whereas using Nrf2 inhibitor or Nrf2 knockout cells improves the activity of NF-κB leading to increased production of cytokines [35]. Additionally, NF-κB and Nrf2 compete also for the transcriptional co-activator CREB-binding protein (CBP) [9] (Figure 2) .

3. 산화 스트레스와 IBD
IBD는 궤양성 대장염과 크론병으로 구성된 장의 특발성 만성 재발성 염증성 질환입니다[5]. 두 질환 모두 유전적으로 취약한 개인의 장내 미생물에 대한 과민한 면역 반응으로 인해 발생합니다[26]. 궤양성 대장염은 대장에 국한된 반면, 크론병은 비연속적인 방식으로 위장관 전체에 염증이 발생하는 것으로 간주됩니다 [5,27]. IBD의 정확한 병인은 수십 년 동안 연구되어 왔지만 아직 명확하게 밝혀지지 않았습니다.

유전적 요인, 면역 체계, 환경적 요인 등

다양한 요인의 상호 작용이 장의 항상성(예: 산화 스트레스)을 방해하여

장 조직의 염증 반응을 유발합니다[4,28].

수많은 연구 결과에 따르면 IBD는 반응성 종의 생산 증가와 관련이 있다고 합니다. 정확히 말하자면, 대장염 동물 모델을 대상으로 한 여러 연구에서 슈퍼옥사이드, 과산화아질산염, 차아염소산, 과산화수소를 포함한 반응성 종의 형성이 증가하는 반면, 대장 조직에서 글루타티온 및 Cu/ZnSOD와 같은 내인성 반응성 종 관련 화합물의 수준은 감소하는 것으로 입증되었습니다 [28]. 항산화 효소의 적절한 변형을 선택하기 위해 유전자 변형 동물 모델을 사용한 연구는 산화 스트레스와 IBD 사이의 인과 관계에 대한 가장 설득력 있는 증거였습니다 [29]. 예를 들어, 형질전환적으로 과발현된 Cu/ZnSOD는 DDS로 유발된 대장염을 현저히 약화시켰습니다. GPx1과 GPx2 또는 추가적인 글루타치온 생합성 억제제(예: 부티오닌 설폭시민)의 결핍은 생쥐에서 대장염을 유발했습니다 [28,30].

산화 스트레스는

장 상피 세포를 직접적으로 손상시킬 뿐만 아니라

면역 세포에서 염증 반응성 종에 민감한 경로의 조절 장애를 일으킵니다 [7].

NF-κB 신호와 Nrf2 신호 경로는

산화 스트레스와 염증에 대응하는

광범위한 생물학적 기능을 조절하는 두 가지 주요 전사 경로입니다 [9].

다중 서브유닛 전사인자 NF-κB는

선천성 및 후천성 면역 체계의 여러 측면에서 중추적인 매개체 역할을 합니다.

이 인자는

사이토카인과 케모카인을 암호화하는

일련의 전 염증성 유전자의 발현을 조절합니다.

또한

NF-κB는

면역 세포의 생존, 이동 및 분화를 지시합니다.

반응성 종은

NF-κB 경로의 단백질, 지질, 다당류 및 핵산과 반응할 수 있지만,

이 경로는 분자에 민감합니다[6].

한 고전적인 연구에서 NF-κB는 마이크로몰 농도의 H2O2에 반응했으며 이러한 활성화는 항산화제 N-아세틸 시스테인(NAC)으로 처리하여 역전되었습니다 [31]. NF-κB가 IBD 환자의 발병과 관련이 있다는 강력한 증거가 있습니다. IBD 환자의 염증성 대장 조직에서 NF-κB 전구체, NF-κB, NF-κB 자극 면역 수용체(예: NOD2) 및 하향 조절 유전자(예: 인터루킨(IL)-12, IL-23)의 조절이 발견되었습니다 [30].

반면에

Nrf2는

다른 전사 인자 계열에 속하며

일련의 항산화제와 해독 효소를 유도할 수 있습니다 [3].

이 인자에 의해 유도된 항산화 단백질의 전사는

과잉 생산된 반응성 종의 축적을 방지할 수 있습니다.

가장 많이 연구된 Nrf2 관련 단백질 또는 단백질 서브유닛은 NAD(P)H, 헴 산소화 효소-1(HO-1), 탈수소효소 퀴논 1(NQO1), 촉매 서브유닛(GCLC), γ-글루타밀 시스테인 리가제 조절 서브유닛(GCLM) 등이 있습니다. 또한 IL-6, IL-1β, IL-17과 같은 전 염증성 사이토카인, 매트릭스 메탈로프로테아제(MMP)를 포함한 세포 외 매트릭스 분해 단백질 및 오토파지 조절과도 관련이 있습니다[32,33]. 또한 Nrf2의 세포 수준은 엄격하게 조절됩니다. 예를 들어, 켈치 유사 ECH 관련 단백질1(Keap1)-컬린2-Rbx1 복합체와의 결합은 Nrf2 유비퀴틴화를 유발합니다. Nrf2/Keap1 복합체의 안정성은 산화 스트레스에 민감한 반면, Keap1 단백질은 반응성 종에 의해 변형될 수 있는 27개의 시스테인 잔기를 포함하고 있습니다 [34]. 흥미롭게도 산화 스트레스 조건에서 NF-κB와 Nrf2 경로의 복잡한 상호 작용은 전사 또는 전사 후 메커니즘에 의해 동적 반응의 미세 조정을 야기할 수 있습니다. 예를 들어, NF-κB는 Nrf2 전사 및 활성을 직접 조절하는 반면, Nrf2 억제제 또는 Nrf2 녹아웃 세포를 사용하면 NF-κB의 활성이 향상되어 사이토카인의 생산이 증가합니다 [35]. 또한 NF-κB와 Nrf2는 전사 공동 활성화제인 CREB 결합 단백질(CBP)을 놓고도 경쟁합니다 [9] (그림 2) .

Figure 2. Schematic representation of the inflammatory response of antioxidant pathways in the intestinal environment. In the immune cells, oxidation stress can enhance the dissociation of the NF-κB/IκB complex and the Nrf2/Keap1 complex, which cause the induction of pro-inflammation genes (e.g., cytokines, chemokines) and antioxidant genes (e.g., enzymes). The crosstalk between these two pathways through a complex molecular interaction plays an important role in IBD. NF-κB—nuclear factor-kappaB; Ub—ubiquitination; CBP—CREB-binding protein; Nrf2—NF-E2p45-related factor 2; Keap1—Kelch-like ECH-associated protein 1; ARE—antioxidant responsive element. Created by BioRender.com.

Above all, oxidative stress plays an important role in the generation and development of IBD. Therefore, besides the conventional methods, targeting the oxidative stress in the intestine by either diminishing the overproduced reactive species or managing antioxidant pathways can effectively treat the disease.

4. Antioxidative Nanotherapeutic Approaches for IBD

The classical IBD treatment contains anti-inflammatory drugs (e.g., 5-aminosalicylic acid, glucocorticosteroids), immunosuppressive agents (e.g., azathioprine, 6-mercaptopurine), and anti-tumor necrosis factor (TNF)-α monoclonal antibodies (e.g., infliximab, adalimumab) [36,37,38]. Unfortunately, because of non-specific distribution and low retention time, direct administration of the current drugs has the potential to cause side effects and fails to diminish symptoms for a considerable number of patients. As mentioned above, antioxidants, or the compounds targeting oxidative pathways, are capable of balancing oxidative stress and effectively treating IBD. Although experimental and clinical investigations proved the benefits of antioxidants, only limited success has been achieved because of the subsequent challenges. First, the gastrointestinal tract is an enzyme-abundant microenvironment with changeable pH conditions. Thus, the activities of many antioxidants may be significantly compromised. Second, the antioxidants are limited to on-site accumulation [17]. For that reason, many antioxidative NP-mediated strategies have been considered as a remarkably promising platform for IBD treatment. As the physiochemical properties of the NPs (size, surface charge, and surface functionalization) have a strong influence upon their permeation, distribution, and cellular uptake, several targeting strategies to design nanocarriers for IBD treatment are employed [39]. The size-dependent accumulation of NPs is mostly studied. To be more concrete, since intestinal inflammation induces the enlarging of tight junctions and increasing permeability, NPs with appropriate sizes can passively accumulate at the inflammatory site [40]. The surface charges are another important character that needs to be tuned for the NPs designed for IBD treatment. The optimal surface charges for them are negative, because the targeting inflammation of the colonic mucous membrane is accumulated of positively charged proteins [41]. Another welcomed delivery strategy is to develop NPs responses to high levels of reactive species at the intestinal inflammatory area [42]. On the other hand, chemical and molecular mechanisms of the delivered antioxidants also have a strong impact on the therapeutic effect. In the following sections, the IBD nanomedicines will be introduced and summarized according to the classification of transported antioxidants (Table 1) (Figure 3).

4. IBD에 대한 항산화 나노치료 접근법

고전적인 IBD 치료에는

항염증제(예: 5-아미노살리실산, 글루코코르티코스테로이드),

면역 억제제(예: 아자치오프린, 6-메르캅토퓨린),

항종양괴사인자(TNF)-α 단일 클론 항체(예: 인플릭시맙, 아달리무맙) [36,37,38] 등이 포함됩니다.

안타깝게도

비특이적 분포와 낮은 유지 시간으로 인해

현재 약물의 직접 투여는

부작용을 일으킬 가능성이 있으며

상당수의 환자에서 증상을 완화하지 못합니다.

위에서 언급했듯이

항산화제 또는 산화 경로를 표적으로 하는 화합물은

산화 스트레스의 균형을 맞추고

IBD를 효과적으로 치료할 수 있습니다.

실험 및 임상 연구를 통해 항산화제의 효능이 입증되었지만, 다음과 같은 문제점으로 인해 제한적인 성공만 거두었습니다.

첫째,

위장관은 효소가 풍부한 미세 환경으로

pH 조건이 변화할 수 있습니다.

따라서

많은 항산화제의 활동이

크게 손상될 수 있습니다.

둘째,

항산화제는

현장 축적으로 제한됩니다[17].

이러한 이유로 많은 항산화 NP 매개 전략이 IBD 치료를 위한 매우 유망한 플랫폼으로 간주되어 왔습니다. NP의 생리화학적 특성(크기, 표면 전하, 표면 기능화)이 투과, 분포, 세포 흡수에 큰 영향을 미치기 때문에 IBD 치료를 위한 나노 담체를 설계하는 여러 표적 전략이 사용되고 있습니다[39]. 크기 의존적인 NP의 축적이 주로 연구되고 있습니다. 좀 더 구체적으로 말하면, 장의 염증은 단단한 접합부의 확대와 투과성 증가를 유도하기 때문에 적절한 크기의 NP는 염증 부위에 수동적으로 축적될 수 있습니다 [40]. 표면 전하 또한 IBD 치료를 위해 설계된 NP를 위해 조정해야 하는 또 다른 중요한 특성입니다. 대장 점막의 표적 염증은 양전하를 띤 단백질로 축적되기 때문에 최적의 표면 전하가 음전하입니다 [41]. 또 다른 환영받는 전달 전략은 장 염증 부위에서 높은 수준의 반응성 종에 대한 NP 반응을 개발하는 것입니다 [42]. 한편, 전달된 항산화제의 화학적 및 분자적 메커니즘도 치료 효과에 큰 영향을 미칩니다. 다음 섹션에서는 운반된 항산화제의 분류(표 1)에 따라 IBD 나노 의약품을 소개하고 요약합니다(그림 3).

Figure 3. Multiple antioxidant nanomedicines are designed to scavenge the overproduced reactive species (non-enzymatic antioxidants) or enhance the catalyzation of antioxidant processes (enzymatic antioxidants), leading to attenuate the inflammation within the gut. In order to specifically target the inflammatory site (intestinal epithelial cells or the intestinal immune system), the size, shape, surface charge, and surface functionalization should be taken into consideration. The classification of the generally-used antioxidants to treat IBD has been summarized. IBD—inflammatory bowel disease.

여러 항산화 나노 의약품은 

과잉 생산된 반응성 종(비효소성 항산화제)을 제거하거나 

항산화 과정(효소성 항산화제)의 촉매 작용을 강화하여 

장내 염증을 약화하도록 설계되어 장내 염증을 완화합니다. 

염증 부위(장 상피 세포 또는 장 면역계)를 구체적으로 표적화하기 위해서는 크기, 모양, 표면 전하, 표면 기능화 등을 고려해야 합니다. IBD 치료에 일반적으로 사용되는 항산화제의 분류를 요약했습니다. 

IBD-염증성 장 질환.

Table 1. Examples of new innovative antioxidant nanotherapeutic approaches against IBD within the last 5 years.

4.1. Nanosystem Delivery of Protein and Peptide Drugs to Impact Oxidative Stress

Oral administration of proteins and functional peptides is particularly challenging for therapeutic approaches to IBD treatment because of their instability in the gastrointestinal tract. Nevertheless, some researchers reported nanoplatforms to encapsulate poor soluble proteins, which are native antioxidant enzymes, naturally derived products with antioxidant activities, or immune system-specific targeting antibodies [22,43,44,45,46,47]. Zen et al. reported SOD and CAT can be directly one-step co-loaded in the nanoparticles and self-assembled by amphiphilic wind chimes like cyclodextrin (WCC) in an aqueous solution under physiological conditions. SOD/CAT co-loaded WCC NPs could not only maintain the activity of endogenic SOD and CAT but also effectively promote the cellular uptake of exogenous antioxidant enzymes. Consequently, the ability to scavenge reactive species, produced by lipopolysaccharide treated macrophages, was increased. The secretion of inflammatory factors decreased, indicating inflammation was inhibited [43]. Another economic protein NP product has been investigated as a carrier for this application as well. In 2019, Huang and coworkers designed NPs by associating chitosan with fucoidan, an anionic long chain sulfated polysaccharide obtained from brown algae for targeting the delivery of soluble eggshell membrane protein (SEP). SEP is extracted from egg products and shows antioxidant and anti-inflammatory activities in intestinal tissues. The chitosan and fucoidan-formed NPs protected the protein from acidic degradation and controlled its release by the response to pH variation in the gastric intestinal tract. Furthermore, the antioxidant activities of encapsulated SEP were significantly enhanced [43]. Administration of TNF-α antibodies is another promising class of drugs owing to enormous achievement in the treatment of inflammatory diseases [41,44]. TNF-α plays a crucial role in IBD, since it is the main pro-inflammatory cytokine primarily secreted by macrophages further targeting the mitochondrial metabolism and leading to an augmented consequence during IBD [77]. However, the immunosuppression caused by systemic exposure to antibodies leads to adverse effects as well as low efficiency. In order to improve antibody therapy for IBD, Yang and coworkers recently demonstrated a nano-platform to orally deliver TNF-α antibody, infliximab, by using hydrogen bonding supramolecular NPs assembled with tannic acid and 1,2-distearoy-sn-glycero-3-phsphoethanolamine-N-[methoxy(polyethylene glycol)] (DSPE-PEG). In this way, Infliximab was protected in the intestinal tract without denaturation/degradation and targeted the intestinal inflammatory site with a high level of reactive species. Thus, a significantly increased therapeutic strategy compared to unprotected antibodies was achieved [44].

In comparison with the proteins, peptides have a smaller molecular size and better solubility in the physiological aqueous environment. The encapsulation of peptides into NPs could ensure that the peptides are more stable and effective due to targeted delivery and sustained release. For instance, naturally occurring tripeptide KPV (Lys-Pro-Val), derived from α-melanocyte-stimulating hormone (MSH), shows anti-inflammatory effect and antioxidative properties on treating colitis. However, the tripeptide is not stable in the intestinal environment without protection. For that reason, Xiao et al. fabricated KPV-loaded hyaluronic acid (HA)-functionalized PLGA NPs with a negative surface charge and desirable size (approximately 270 nm). NPs were biocompatible with intestinal cells and accelerated mucosal healing by attenuating inflammation. The NPs were further loaded in the chitosan/alginate hydrogel system. The HA-KPV NPs encapsulated chitosan/alginate hydrogel system displayed a strong capacity to protect mucosa and down-regulate TNF-α. The results demonstrated that the nano-in-gel system can long-term release HA-KPV NPs in the colon. Then the NPs penetrated colitis tissues and enabled antioxidative tripeptide internalization to alleviate inflammation [47].

4.2. Nanosystem Delivery of Nucleic Acid Drugs to Interfere with Antioxidant Pathways

The development of another macromolecule, nucleic acids’, delivery nanomaterials is attracting great attention in antioxidant therapy. The nucleic acids-mediated antioxidative nanotechnology has the potential to precisely inhibit oxidative stress-induced molecular damages, meanwhile, unexpected interference can be avoided [78]. The nanocarriers are typically designed for oral administration, which is the most appropriate and cost-effective approach to deliver encapsulated nucleic acid to gastrointestinal tissues [43,79]. Therapeutic nucleic acids such as messenger ribonucleic acids (mRNAs), micro ribonucleic acids (miRNAs), and small interfering ribonucleic acids (siRNAs) can be delivered by nanocarriers to regulate oxidative stress-related genes for IBD treatment. Since the physicochemical properties of polymers can be carefully tuned, the utility of functional polymers as intracellular delivery systems for nucleic acids has been wildly used in clinical trials [80]. Various polymers such as modified nature-derived polymers, amphiphilic copolymers, and siRNA-polymer conjugates can condense the nucleic acids (negatively charged and hydrophilic) into the carriers via electrostatic interactions and hydrophobic interactions [79].

In 2018, the modified mRNA molecule for expressing a desired anti-inflammatory cytokine (e.g., IL-10) was developed by Dan Peer and his coworkers to effectively treat IBD. The modified mRNA-loaded lipid NPs were mainly formed by distearoylphosphatidylcholine(DSPC), cholesterol, 1,2-Dimyristoyl-rac-glycero-3-methoxy(DMG)-PEG and 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine(DSPE)-PEG. In order to precisely target Ly6c+ inflammatory leukocytes, the NPs were further functionalized by anti-Ly6c monoclonal antibodies [48].

MiRNAs are endogenous single-stranded non-coding RNAs (approximately 22 nucleotides). They act on post-transcriptional regulators of gene expression‎ [81,82]. Recently, miRNAs have been found to regulate responses to oxidative stress. A significant number of publications have described the targeting of miRNAs on the Nrf2 pathways or GSH biosynthetic enzymes [83,84]. Therefore, the delivery of miRNAs or synthetic miRNA inhibitors by nanotechnology can be promising medical treatments of IBD. For instance, miRNA-31 has been found to be elevated in colon tissues from both Crohn’s patients and colitis patients. MiRNA-31 inhibitors or miRNA-31 inhibitors/curcumin encapsulated α-lactalbumin NPs in Konjac glucomannan (sOKGM) microspheres successfully reduced features of colitis and further treated colorectal cancer [49].

Similar to miRNAs, siRNAs also have the potential to treat wide-ranging classes of diseases, because they are capable of reversibly silencing target genes [85]. Several studies have documented that targeted siRNA nanocarriers ensured the penetration of siRNA from the surface of inflamed tissue into the immune system. siRNAs could target macrophage cells, directing against pro-inflammatory cytokines (e.g., TNF-α) and cytokines related kinase (e.g., mitogen-activated kinase kinase kinase kinase 4 abbreviated as Map4k4) to treat intestinal inflammatory diseases [41,50,51,86,87]. Given the important role of TNF-α in IBD progression, Murthy and his co-workers operated a thioketal delivery system, which locally released TNF-α siRNA in response to reactive species at the site of inflammation to treat DSS-induced colitis in mice. The nanomaterial was formed from a polymer, poly-(1,4-phenyleneacetone dimethylene thioketal) (PPADT), which enabled the protection of siRNA from the harsh environment. Most importantly, PPADT NPs degraded selectively in response to reactive species. Taken together, the TNF-α siRNA-loaded PPADT NPs effectively silenced TNF-α expression‎ in mice suffering from colitis [88]. Since then, the smart reactive species-response polymer has made a significant contribution to the treatment of numerous gastrointestinal inflammatory diseases such as IBD and gastrointestinal cancers. In the subsequent studies, galactosylated low molecular weight chitosan (gal-LMWC), mannosylated poly (amido amine)/sodium triphosphate (TPP), calcium phosphate (CaP)/poly (lactic acid-co-glycolic acid) (PLGA), poly(ethylene glycol)-block-poly(lactic-co-glycolic acid)(PEG-b-PLGA)/cholesterol, poly(lactic-co-glycolic acid)(PEG-b-PLGA)/galactosylated chitosan and poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTG-PEI)) triblock copolymer have also been reported in the literature as TNF-α siRNA carriers to treat colonic inflammatory diseases [25,41,50,51,89,90]. The TNF-α siRNA-loaded NPs were also used as a matrix for the co-delivery of inflammatory drugs such as dexamethasone sodium phosphate (DXMS) and curcumin [50]. Studies also showed that the regulation of Map4k4 not only mediated TNF-α signaling but also promoted its expression‎. Upon oral administration, the Map4k4 siRNA, encapsulated in galactosylated trimethyl chitosan-cysteine (GTC)/tripolyphosphate (TPP) or GTC/HA NPs, significantly decreased the expression‎ of TNF-α in colonic cells and related parameters in the DSS-induced colitis in a mouse model [91,92].

4.3. Nanosystem Delivery of Small-Molecule Antioxidants to Act as Reactive Species Scavengers

Both natural and synthetic small-molecule antioxidants have been widely studied for IBD treatment. The commonly used natural antioxidants include bilirubin, polyphenols, flavonoids, genipin, glutathione, etc., whereas synthetic antioxidants are edaravone, lipoic acid, NAC, 4-Hydroxy-2,2,6,6-tetramethylpiperidinyloxyl (Tempol), etc. [17].

Given that naturally derived antioxidants are vulnerable, researchers have attempted to develop naturally derived antioxidants delivery nanomaterials. As a result, antioxidants can be effectively delivered to specific inflammatory intestinal sites [78]. For example, bilirubin has been suggested as a potent endogenous antioxidant that is capable of scavenging reactive species to protect cells/tissues from oxidative damage. Although the physiological role of bilirubin has been investigated for decades, the clinical application of bilirubin has been restricted due to its poor water solubility [71,93,94,95]. To overcome the critical problem of natural bilirubin, Jon and his coworker worked on PEGylated bilirubin NPs. The self-assembled particles, with a diameter of approximately 110 nm, are highly efficient hydrogen peroxide scavengers, which protect cells from hydrogen peroxide-induced damage. In vivo, the PEGylated bilirubin NPs showed preferential accumulation at the inflammatory site and significantly inhibited the inflammatory response in the colon [94,95]. Moreover, another bilirubin-derived NP, HA-bilirubin, has been developed. The NPs accumulated in the inflamed colonic epithelium in mice and have multiple positive effects including restoring epithelium barriers, augmenting the overall abundance of gut microbiota, and effectively regulating innate immune responses [71].

Moreover, polyphenols are a large family of phytochemicals that are abundant in food and derived from plants characterized by multiples of phenol units. However, their drawbacks such as intrinsic poor water solubility and low bioavailability after generally oral administration need to be overcome. The utility of polyphenol in nano-formulations aims to improve its solubility, activity, and stability, making the compound therapeutically more effective without adverse effects. Many nano-encapsulated polyphenols (curcumin, resveratrol, berberin, epigallocatechin gallate (EGCG), tannic acid, rosmarin acid, oleuropein, and ginsenoside) have recently been proved to have anti-inflammatory properties and have an important role in the management of IBD [10,52,53,54,55,56,57,58,59,60,61,62,67]. For the same reason, the polyphenol-rich extracts such as grape seed extract, green tea extract, and lycin barbarum extract have the potential to treat intrinsic inflammation as well [66,68,69,70]. Currently, a compound used worldwide is curcumin, which is derived from Curcuma longa extracts. Regarding its antioxidant and anti-inflammatory effects, multiple treatments have been remarkably highlighted [96]. To overcome the drawbacks of curcumin, a novel fibroin/chitosan-based macrophage-targeted curcumin delivery system was developed by Gou et al. The fibroin/chitosan NPs have well-controlled size distribution (approximately 175.4 nm), negative surface charge, and effective curcumin encapsulating. Upon the stimulation by pH/GSH/reactive species, curcumin can be controlled released. Due to the surface characteristics of the NPs, they can specifically recognize and bind to the glycoprotein CD44 on the surface of macrophages. As a result, the cellular uptake capacity of NPs is improved through the CD44 mediated endocytosis pathway. Through both oral administration and intravenous therapy, the particles could improve the specific internalization and exhibit controlled release of the compound [58]. In addition, HA-functionalized chitosan/PLGA, hydrophilic Eudragit® S100, hydroxyethyl starch-curcumin conjugates, genipin-crosslinked human serum albumin, chitosan/sodium alginate/cellulose acetate phthalate polyelectrolyte multilayer, and α-lactalbumin/sOKGM have been recently explored to encapsulate or co-encapsulate curcumin for IBD treatment [56,57,59,87,97,98].

Accumulating studies have reported that flavonoids (e.g., quercetin, catechin, silymarin) showed beneficial effects in treating IBD [63,64,66]. The reasons for the powerful effects are first, that they can act as strong antioxidants, and second, that they can act as cellular modulators of protein kinase and lipid kinase signaling pathways. [99] Most recently, genistein has been delivered by β-cyclodextrin(β-CD) and 4-(hydroxymethyl)phenylboronic acid pinacol ester-modified genistein nanosystems (defined as Gen-NP2). Gen-NPs could effectively release genistein to the inflamed colon instead of absorption by the stomach or intestines. Gen-NPs effectively scavenged reactive species and regulate the inflammasome-autophagy pathway. Spontaneously, gut microbiota were modulated. Eventually, intestinal mucosal healing and barrier integrity were promoted [65].

On the other hand, synthetic antioxidant compounds can also be potentially useful in IBD therapy. The synthetic antioxidant-loaded NPs not only have enzyme-mimicking functions but also spontaneously scavenge reactive species during the catalyzing [17]. Thus, they have been engineered as another type of candidate for IBD treatment. Nagasaki designed a ROS-nitroxide radical-containing particle (RNPo), having a diameter of 40 nm, by establishing an amphiphilic block copolymer with Tempol, which is a stable nitroxide radical-containing ROS trapper. They could specifically accumulate in the IBD model. In comparison with Tempol and 5-aminosalicyclic acid, RNPos were more effective in reducing inflammation. The RNPos could further load silymarin, an active compound with anti-inflammatory and antioxidant properties, resulting in a synergic effect for the recovery in the colonic mucosa of the DSS-induced model [100]. A different approach was followed by Zhang and coworker. They fabricated a series of SOD/CAT-mimetic nanomedicine based on PBAP-conjugated β-CD material. Tempol and annexin A1-mimetic peptide Ac2-26 were effectively packed into smart-responsive nanocarriers. Benefiting from the protection and site-specific accumulation of the nanomaterial, both Tempol and Ac2-26 were control released at the inflammatory sites. Owing to the therapy by RBAP-conjugated β-CD-based nanomaterial, the inflammatory symptoms were reduced, the wound healing of intestinal mucosal accelerated, and the composition of gut microbiota reshaped [45]. Another method is to develop a nanoscale prodrug. IBD targeting Janus-prodrug (Bud-ATK-Tem) was conjugated by the anti-inflammatory drug budesonide (Bud) conjugated ROS-responsive aromatized thioketal (ATK) and Tempol. Due to macromolecular interaction, hydrophobic interactions, and π-π interaction of the amphiphilic conjugate, the prodrug self-assembled into NPs with the size of approximately 100–120 nm. The 98% drugs (Bud and ATK) were released in the inflammatory macrophages. In the DSS colitis model, the drug-loaded NPs were passively accumulated in the inflamed tissue, thus ensuring they can improve the antioxidative and anti-inflammatory efficacy [101].

4.4. Nanozymes to Catalyze Oxidative Defense

Some specific metals and metal oxides have inherent enzymatic properties which have been known for decades. In 2007, Yan and coworkers investigated iron oxide formed peroxidase mimic nanomaterials. Since then, metal-based antioxidative nanomaterials were defined as nanozymes [102]. The new generation of artificial enzymes not only has the advantages of unique properties of nanomaterials but also exhibits high catalytic activity, superior stability, and economical price, among others. Therefore, various nanomaterials formed with metals and metal oxides have been rapidly studied and industrialized for therapeutic applications [103]. As mentioned above, Se represents the most significant part of the active center of antioxidant enzymatic activities (selenoproteins) [104]. To date, various Se-based compounds have attracted great attention due to their inherent antioxidant enzyme-like property. Se-NPs produced by L.casei ATCC 393 significantly alleviated the increase of reactive species and maintained permeability of intestinal epithelial cells (NCM460 cell line). Particularly, the Se-derived NPs diminished the ultrastructure damage of mitochondria caused by oxidant stress [72]. Besides the above-mentioned nanozymes, some other inorganic NPs have also been investigated, such as NPs derived from Prussian blue, manganeses (Mn), Cerium oxide (CeO2), ZnO, and Gold (Au) [11,18,19,20,50,73,74,75,76]. A remarkable work was reported by Chen and coworkers, who synthesized Mn-Prussian blue NPs with multi-enzyme-like properties to mediate catalytic IBD therapy. Owing to the positively charged artificial surfaces and desired sizes, NPs significantly improved colitis in mice via the toll-like receptor (TLR) signaling pathway with no adverse effects [18]. Another notable versatile nanozyme for biological application was CeO2 NP. Upon the mixed-valence states between Ce3+ and Ce4+ on the surface of NPs, it has been demonstrated to possess SOD and CAT-mimetic activity as well as the activities of scavenging reactive species. Due to the presence of surface oxygen vacancies, Ce4+ can be reduced to Ce3+, resulting in effectively decreasing ROS levels [105]. An in situ growth NPs was performed by Zhao and coworkers. They reported a system for IBD treatment coupled with multi-enzyme mimicking CeO2 NPs and montmorillonite (MMT). When the CeO2/MMT ratio was 1:9, the nanozyme was stable in the gastric tract by oral administration. The NPs were more effective and stable than free enzymes. Moreover, upon electrostatic interactions, negatively charged MMT was associated with specific targeting to positively charged inflamed colon tissue [19].

5. Conclusions and Prospects

To date, IBD has evolved into a worldwide disease in not only developed countries but also newly industrialized countries [106]. Accumulated studies suggest that IBD is caused by commensal microbe-induced continuing inflammation in a genetically vulnerable host [26]. During the inflammatory process, the inflammatory cells related to the immune system secrete a large number of cytokines and chemokines, which stimulate reactive species overproduction and eventually cause oxidative stress [5]. Given oxidative stress plays a crucial role in the pathogenesis of IBD, multiple antioxidant therapeutic strategies are being explored including the removal of reactive species, enhancing the synthesis of antioxidant enzymes, mimicking the antioxidant enzymes, and the inhibition of abnormal redox signaling for reactions.

Engineering materials with either naturally derived polymers or synthetic polymers at the nanoscale enables the arrangement of several above-mentioned strategies into one delivery system with multicomponent and multifunction. In other words, using nanotechnology can spontaneously co-carry antioxidant pathways related macromolecules (proteins, peptides, and nucleic acids) and small molecules (antioxidants and metal oxides) to treat IBD. Meanwhile, many benefits can be achieved, including improving the delivery of poorly water-soluble antioxidants, targeting delivered drugs in an inflammatory manner, and transcytosis of functional compounds across the epithelial barriers to immune cells [39]. However, to successfully translate current nanotherapeutic approaches from laboratory investigation to clinical application, numerous limitations still need to be overcome. In general, minimizing the batch-to-batch variation, improving pharmacokinetic properties, enhancing loading efficiency, handling cost-efficiency, and simplifying synthesis progress are key points.

There are several concerns and challenges associated with antioxidant monotherapy for IBD treatment. First, oxidative stress might not be the primary contributor to disease. In other words, avoiding overproduced reactive species may not have a key impact on the progression of inflammatory diseases. Thus, future experimental and clinical studies should not only eval‎uate the therapeutic efficacy of the antioxidants (macromolecules or small molecules) alone but also study the synergic effects of antioxidants, combined with conventional drugs and engineered stem cells (e.g., allogeneic expanded adipose-derived mesenchymal stem cells). Second, complex pathophysiological mechanisms should be taken into consideration. Systematic exploration of protein complex composition and network analysis between NF-κB and Nrf2 pathways can provide new insight to manipulate IBD [9]. To our knowledge, the crosstalk of Nrf2 and NF-κB has not been systematically investigated. In the coming future, researchers can focus on the direction of the crosstalk between the NF-κB and Nrf2 pathways by nanotechnology. Third, future studies should also define the correlation between the endogenous attenuation of oxidative stress and exogenous antioxidant treatment. It should always be kept in mind that reactive species have important physiological functions, especially in immunity against pathogenic microorganisms. The ideal antioxidant-based therapeutic approaches should be designed and eval‎uated precisely to decrease oxidative damage without significantly diminishing the influence of reactive species on physiological activities. Last but not the least, researchers can also cooperate with the diagnostic materials (e.g., graphene quantum dot) in addition to the antioxidant nanomaterials [107]. Thus, multifunctional antioxidative nanomedicines can monitor the pharmacokinetics and pathological process for designing accordingly personalized antioxidant therapy.

Author Contributions

X.W. received the initial invitation to write a review on this topic; writing—original draft preparation, P.L.; writing—review and editing, Y.L., R.W., F.R. and X.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

No applicable.

Informed Consent Statement

No applicable.

Data Availability Statement

No applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References