Introduction

Acute pancreatitis (AP) is a potentially fatal disease with high morbidity and mortality[1]. The typical clinical symptom is persistent severe pain in the epigastrium with abdominal distension, nausea and vomiting. In recent years, its incidence has increased over time [2, 3]. Gallstones and alcohol are common causes of AP [4], leading to activation of trypsinogen, which further activates other digestive enzymes and causes self-digestion in the pancreas [5]. In terms of the course of the disease, it progresses rapidly and the patient develops moderate AP (MAP) or severe AP (SAP), resulting in infectious necrosis, systemic inflammatory response syndrome (SIRS), and multiple organ dysfunction syndrome (MODS), with a mortality rate of 20–40% [6, 7]. Currently, the diagnosis of AP mainly relies on laboratory tests and imaging examinations, which have lower sensitivity for detecting early AP, leading to a decrease in the diagnostic rate of AP and aggravation of the disease. In terms of treatment, general therapy for AP includes close monitoring of vital signs, fluid balance, pain relief, nutritional support, and infection prevention [7, 8]. However, these methods usually fail to suppress the early response of SIRS and prevent subsequent organ failure, and no effective treatment for AP is currently available [9]. Thus, there is an urgent need for a new strategy for the diagnosis and treatment of AP.

The occurrence of AP is a complex, multifactorial, pathophysiological process. Pathological calcium signaling, mitochondrial dysfunction, impaired unfolded protein response, endoplasmic reticulum (ER) stress, and impaired autophagy are among the multiple factors contributing to the pathophysiological changes in the pancreas [5, 10]. The main pathological changes in the pancreas include the activation of trypsin, aggregation of inflammatory cells, and the excessive release of proinflammatory factors and reactive oxygen species (ROS), along with other factors, producing an abnormal microenvironment. These in turn result in a systemic inflammatory response and extensive pancreatic injury. Therefore, the identification and regulation of relevant indicators of the inflammatory microenvironment may be the key to diagnosing or treating pancreatitis.

In recent years, researchers have made remarkable progress in both the diagnosis and the treatment of AP by develo** highly sensitive diagnostic tools and drugs targeting microenvironmental changes. Among these approaches, nanotechnology has attracted widespread attention because of its advantages of high sensitivity, specificity, multimeasurement ability, and targeted therapy [11]. Specifically, nanotechnology can target indicators in the microenvironment for the diagnosis and modulation of a disease. For example, Cheng et al. designed an MMP-13/pH-responsive nanoprobe (CMFn@HCQ) for the diagnosis and treatment of inflammation [12]. It was also reported that ferritin nanocages (CMFn) can be used for fluorescence imaging in response to the overexpression of metalloproteinases (MMP-13), a group of protein hydrolases that are related to the degree of inflammation in the microenvironment. It was also shown that the CMFn@HCQ nanocages could release hydroxychloroquine (HCQ) continuously into an acidic microenvironment, which significantly reduced local inflammation. ROS, as free radicals, are closely related to inflammation. The imaging and regulation of ROS can realize the early diagnosis and treatment of AP. Our group also developed a novel nanotheranostic agent (named TMSN@PM) with the ability to target inflammatory sites. Under acidic conditions featuring excessive ROS, TMSN@PM was shown to degrade and release manganese ions for magnetic resonance imaging (MRI) to assess the severity of inflammation. It was found that the T1-weighted signal was enhanced in the pancreatic region, which peaked 3 h after TMSN@PM injection. TMSN@PM also scavenges excess ROS and reduces JNK and hypoxia-inducible factor-1α (HIF-1α) activation, thereby reducing inflammation. Compared with the findings in an untreated group, ROS in the pancreas decreased significantly after TMSN@PM treatment, which attenuated the damage to pancreatic tissue [45]. Nanotechnology can improve the capabilities of MRI by develo** macrophage-targeted-accumulation contrast agents [46]. As reported previously, a novel Gd-containing contrast agent named Gd(III)-dithiolane gold nanoparticles can be phagocytosed by macrophages for targeted accumulation in the pancreas, which showed a very high r1 relaxation rate at both low and high magnetic field strengths for MRI of the pancreas[47]. Decorating nanoparticles with ligands that bind to macrophage surface receptors can improve the targeting of nanoparticles. Since mannose receptors are highly expressed by macrophages, Tian et al. developed novel Gd-DTPA-loaded mannosylated liposomes (named M-Gd-NL) (Fig. 2A). M-Gd-NL can bind to macrophages in a targeted manner in the inflammatory microenvironment and then release Gd-DTPA, resulting in a potent increase in the relaxation rate of Gd-DTPA in macrophages, which substantially enhances the capacity of MRI. This method not only improves the diagnostic capability of MRI, but also enables differentiation between mild and severe AP [48]. Similarly, Long et al. synthesized a P-selectin-targeted, near-infrared fluorescence (NIRF) dye (Cy 5.5)-labeled dual-modal nanoprobe (Gd-DTPA-Cy5.5-PsLmAb) based on the finding that macrophages highly express P-selectin. When PsLmAb of the nanoprobe can bind P-selectin in the microenvironment, the more P-selectin there is, the more Gd-DTPA-Cy5.5-PsLmAb nanoparticles that reside at the site of inflammation, resulting in an enhanced signal in MR/NIRF images (Fig. 2B). This probe can achieve the early diagnosis and treatment of SAP by MR imaging and NIRF imaging, providing a rapid method of visualization for the diagnosis of clinical early-stage SAP [49].

Fig. 2
figure 2

Copyright 2022, Elsevier

A The preparation procedure of Gd-NL and M-Gd-NL based on lipid film method. Reproduced with permission from reference [48]. Copyright 2017, DOVE Medical Press B Schematic representation of Gd-DTPA-Cy5.5-PsLmAb for NIRF and MR imaging of MAP and SAP. Reproduced with permission from reference [49]. Copyright 2020, American Chemical Society C Schematic illustration of the mechanism of activatable chemiluminescent probes. Reproduced with permission from reference [62]. Copyright 2022, John Wiley and Sons D Fabrication and targeted-therapeutic schematics of ND-MMSNs. Reproduced with permission from reference [63]. Copyright 2018, Springer Nature E Schematic illustration of nanoparticle-encapsulated CQ/TAM combined with MSCs for arresting the increasing severity of AP in mice through iNOS (IDO) signaling. Reproduced with permission from reference [68].

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Macrophages also mediate the pathological process of AP through various mechanisms [50, 51]. It has also been reported that macrophages are related to the progression of SAP [52]. During SAP, peritoneal macrophages, alveolar macrophages, and Kupffer cells are activated, which contribute to the damage to various organs. Macrophages can be divided into two subtypes: M1 macrophages and M2 macrophages. M1 macrophages secrete factors related to the proinflammatory stage of AP, while M2 macrophages are mainly involved in pancreatic repair and regeneration [53]. Macrophages can change their phenotype and function spatiotemporally, which is called macrophage polarization. Therefore, regulating the polarization of macrophages is a new direction for the treatment of AP [54, 55]. Kazuaki et al. constructed a nanotechnology-based CO donor (CO-HbV) that can target macrophages and inhibit AP by releasing CO to polarize macrophages toward an M2-like phenotype. CO-HbV was also reported to inhibit neutrophil infiltration in the pancreas and attenuate the subsequent acute lung injury [56]. The degree of severity of AP is related to the number of infiltrating macrophages, which is involved in the development of injuries to the pancreas and multiple other organs. Based on this, researchers have focused particularly on drugs that inhibit macrophage recruitment and deplete macrophages. Tang et al. studied the protective effects of G4.5-COOH and G5-OH on the pancreatic injury of AP mices. It was found that two kinds of dendrimers reduced the inflammatory infiltration of macrophages by inhibiting nuclear translocation of NF-κB in macrophages. Moreover, they also inhibited the expression of proinflammatory cytokines in peritoneal macrophages and significantly decreased the pathological changes of the pancreas [57]. Clodronate liposomes are the most commonly used method to deplete macrophages [58]. Dang et al. loaded liposomes with clodronate and superparamagnetic iron oxide (SPIO), which can be delivered in a targeted manner to macrophages to induce their apoptosis by competing with adenosine triphosphate (ATP), thus inhibiting the release of inflammatory factors and alleviating the renal injury caused by SAP [59]. Different from them, Chen’s team investigated an inflammation-targeted nanoparticle named MU, which was composed of PEG − PLGA and ulinastatin coated by macrophage membrane [60]. In the mouse model of AP, MU can significantly inhibit the secretion of pro-inflammatory cytokines TNF-α and IL-6 by macrophages. In addition, in vitro experiments have proved that MU may play an anti-inflammatory role by reducing the contents of p-IκBα/IκBα and p-p65/p65 through IκBα/NF-κB signaling pathway. Therefore, MU is expected to be an effective targeted drug to inhibit the progress of AP.

Neutrophil infiltration is a hallmark of inflammation. Neutrophils, as a “living” drug delivery carrier, have attracted widespread attention in recent years because of their characteristics of crossing natural barriers, decreasing immune clearance rate and having a long biological half-life [61]. Similar to macrophages, neutrophils can take up nanoparticles [61]. Therefore, researchers have explored various neutrophil tracking probes for disease diagnosis. For example, Huang’s team synthesized three chemiluminescent probes based on benzoazole-phenoxyl-dioxetane for the in vivo imaging of neutrophils in mouse models of peritonitis and psoriasis. These probes activate and prolong chemiluminescence in the presence of neutrophil elastase (NE) (Fig. 2C). In experiments with LPS-induced peritonitis, benzothiazole-phenoxyl-dioxetane (BTPDNE) exhibited more intense brightness and a longer half-life than methyl acrylate-phenoxyl-dioxetane (MPDNE) [62]. Moreover, Wu et al. developed core–shell structured magnetic mesoporous silica nanoparticles (called MMSNs) and constructed a theranostic platform of ND-MMSNs for internalizing MMSNs loaded with doxorubicin (D-MMSNs) by neutrophils [63]. In the inflammatory mouse glioma model, ND-MMSNs are internalized by neutrophils, which can be targeted to accumulate at the inflammatory site of glioma with chemokines. Then, neutrophils release neutrophil extracellular traps (NETs) and D-MMSNs to realize the diagnosis and treatment of residual tumors (Fig. 2D). Similar to the features of the above diseases, there are a large number of neutrophils in the inflammatory microenvironment of AP, and it is expected that nanoparticles used for neutrophil imaging in the future can be used for the diagnosis of AP.

Neutrophils can release ROS to cause tissue damage [64]. Moreover, the production of NETs can speed up the progression of AP [65]. Neutrophils may serve as a target for the treatment of AP because they can mediate local tissue damage in the pancreas and associated damage to other organs when AP occurs [66]. Nanotechnology provides an plausible pathway for neutrophil-related therapeutic intervention. For example, nucleic acid nanoparticles (tFNAs) were recently reported to regulate cell proliferation and migration, and have potent anti-inflammatory and antiapoptotic abilities against AP. Wang et al. found that compared with a saline group, tFNAs significantly decreased neutrophil activity and alleviated pancreatic injury in a treatment group [67]. Additionally, Liu et al. introduced nanoparticle-encapsulated chloroquine/tamoxifen in combination with bone marrow-derived mesenchymal stem cells (BMSCs) that acted synergistically for the treatment of AP. BMSCs prevented the progression of AP by suppressing the recruitment of neutrophils, macrophages, and CD4+ T cells through iNOS signaling (Fig. 2E) [68]. Furthermore, another membrane-encapsulation technology has been applied for targeting inflammation [69, 70]. Membrane-encapsulation technology can confer nanoparticle-derived cell membrane-related functions such as immune evasion [71], crossing barriers [72], and homing to inflammatory sites [73]. Zhou et al. designed neutrophil membrane-coated nanoparticles (NNPs/CLT) that cross the blood-pancreas barrier (BPB), driven to sites of inflammation through chemokine recruitment, which significantly downregulate the level of pancreatic myeloperoxidase and reduce associated lung injuries in AP rats [74].

Macrophages and neutrophils play an important role in the systemic production of inflammatory mediators. Nanodiagnostic and nanotherapeutic agents targeting neutrophils or macrophages can be designed by nanotechnology to assess the severity of AP and suppress overactive inflammatory responses. At present, notable achievements have been made in the research and development of targeted drugs for macrophages and neutrophils. Since macrophages and neutrophils have abundant surface receptors, the development of more nanoparticles targeting these receptors is a promising future strategy.

Oxidative stress and reactive oxygen and nitrogen species

Oxidative stress is an important factor in the progression of AP, and it generates a large number of free radicals including ROS and reactive nitrogen species (RNS), leading to an imbalance between the oxidative and antioxidant systems [75]. ROS, as free radicals, are closely related to inflammation [4C). In mouse models of mild and severe AP, MΦ-NP(L&K) significantly attenuated alveolar necrosis or immune infiltration and effectively reduced the severity of AP[99].

As biomarkers, digestive enzymes can be used to diagnose AP. Moreover, as important components of the inflammatory microenvironment, they are important to the development of AP and used to regulate the inflammatory microenvironment. Functional composite nanoparticles have multiple roles in the diagnosis and treatment of AP. First, as drug carriers, they can prolong the half-life of drugs; second, they can react with digestive enzymes in the microenvironment to release drugs; finally, they can bind with enzymes covalently or noncovalently to inhibit enzyme activity. Therefore, the design of functional composite nanoparticles targeting the inflammatory microenvironment using the biocatalytic properties of enzymes is extremely promising.

pH

The decrease of pH is one of the characteristics of the inflammatory microenvironment. When AP occurs, enhanced glycolysis of inflamed tissue leads to increased lactate production and a decrease in pH. Impaired endocrine and/or exocrine function of the pancreas in AP patients inhibits bicarbonate secretion by ductal cells, leading to enhanced acidification of the acinar luminal space. Lowering of pH promotes trypsinogen activation by cathepsin B [100], leading to self-digestion of the pancreas. Furthermore, persistent extracellular acidification can disrupt cell junctions and lead to the leakage of zymogen into the interstitial fluid [101]. Thus, extracellular acidification exacerbates the development of AP.

In recent years, pH-responsive drug carriers have achieved good results in the diagnosis and treatment of various diseases including AP by targeting drugs to sites of inflammation and modulating drug release in response to pH stimuli [102, 103]. In terms of diagnosis, Lu et al. synthesized a pH-responsive MRI contrast agent, SPIO@SiO2@MnO2, which can improve the diagnostic accuracy of MRI in an acidic environment by decomposing manganese dioxide (MnO2) into Mn2+ to increase T1- and T2-weighted signals (Fig. 5A) [104]. Experimental results demonstrated that the contrast sensitivity of diseased tissues is about 12.3 times that of normal tissues. As for treatment, Mei et al. developed porous COS@SiO2 nanocomposites that enable the continuous release COSs and maintain the drug at high concentrations in a pH-controlled manner, which helps to reduce the severity of SAP and its associated lung injury [105]. It was found that the release rate of COS was greater at pH 7.4 than at pH 8.0 (Fig. 5B). Yang’s team used chloroquine diphosphate (CQ) for gene transfection to construct Ca-CQ-pDNA-PLGA-NPs that can deliver targeted genes to the site of pancreatitis and protect the pancreas from deterioration based on pH changes. Compared with the findings at pH 7.4 and pH 6.8, the cumulative pDNA release at pH 4.5 exceeded 30% within 24 h and eventually reached 60% within 4 weeks [106]. Similarly, Hassanzadeh et al. prepared a neutrophil membrane-encapsulated nanoformulation (FA-SF-NPs) using silk fibroin (SF) and ferulic acid (FA). FA-SF-NPs released FA with higher kinetics in a low-pH environment compared with the findings at physiological pH, thereby downregulating serum enzymes and oxidative stress-related indicators to reduce the severity of AP [107]. Moreover, with the development of nanotechnology, pH-responsive theranostic nanoplatforms have been successively developed. Dou et al. constructed metal Fe/Ce-doped mesoporous silica nanoparticles (Fe-Ce-MSN) for the treatment of inflammation and oxidative stress-related diseases [108]. In the mildly acidic environment of inflammatory sites, Fe-/Ce-MSN nanoparticles released Fe ions, which enhanced the T2-weighted signals. Additionally, Fe-Ce-MSN NPs not only scavenged overproduced ROS but also controlled the production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), with significant antioxidant and anti-inflammatory effects (Fig. 5C).

Fig. 5
figure 5

Copyright 2022, Frontiers Media S.A

A SPIO@SiO2@MnO2 shows weak T1 and T2 contrast intensity in normal physiological conditions, as the T2 signal of SPIO is quenched by the MnO2 layer. In the acidic environment of a tumor or inflamed tissue, the MnO2 layer will decompose into magnetically active Mn2+ (T1-weighted), and the T1 and T2 signals are sequentially recovered. Reproduced with permission from reference [104]. Copyright 2022, Springer Nature B The cumulative release of COSs from COS@SiO2 at pH 7.4 and pH 8.0. Reproduced with permission from reference [105]. Copyright 2020, Frontiers Media S.A. C Schematic illustration of biodegradation, ROS scavenging effects, and enhanced theranostic functions by Fe/Ce-MSN-PEG NPs. Reproduced with permission from reference [108].

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The inflammatory response of AP fosters a pH gradient between inflamed and healthy tissues, which provides a suitable physiological stimulus for pH-responsive drug delivery. pH-responsive drug delivery systems overcome the shortcomings of conventional drug formulations and show advantages in terms of biocompatibility, stability, size, and structural control. Moreover, they can deliver drugs to specific sites in a controlled manner and at predetermined release rates, reducing drug side effects and improving drug efficacy. Therefore, acid-responsive nanocarriers are of high value for the diagnosis and treatment of AP.

As a brief summary, Table 1 shows the strategies of diagnosis and treatment of AP with various nanomaterials.

Table 1 Nanotechnology-based strategies for the diagnosis and treatment of acute pancreatitis
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Microorganisms

AP can be classified as MAP, moderate-to-severe AP (MSAP), and SAP according to the severity [109]. Patients with AP can develop MSAP and SAP, leading to necrotizing pancreatitis (NP), which has a high mortality rate [110]. In the later stage, patients develop intestinal dysfunction and are at risk of the translocation of intestinal flora and secondary infection of necrotic tissue. Most of the bacteria that cause pancreatic tissue necrosis infections are from the intestinal flora [111], mainly including Gram-negative and Gram-positive bacteria. The gut microbiota exists in the inflammatory microenvironment, which is an important mediator during AP and influences the progression of AP.

New imaging strategies have been developed by those researching infectious diseases [72, 136]. Currently, nanocarriers targeting the inflammatory microenvironment are limited to a single type, resulting in low delivery efficiency. In the future, the advantages of different carriers can be combined to develop carriers with higher delivery efficiency and biosafety. Secondly, the pathogenesis of AP has not been fully clarified, so there are not enough specific targets for AP, resulting in fewer nanodrugs that can specifically enter the pancreatic inflammatory microenvironment. At present, most nanodrugs passively target inflammatory lesions through the ELVIS effect to increase the drug concentration, but there is an off-target effect, which leads to low efficiency of nanodrug delivery [74, 107]. There is an urgent need to develop more active targeted nanodrugs combined with target molecules, instead of passive targeting, and to improve the delivery efficiency. Recently, the emergence of genomics, protein genomics and metabonomics has made it possible to find more specific markers of pancreatitis, thus improving the diagnosis rate and treatment efficiency.

The development and application of functional nanomaterials targeting various potential targets in the inflammatory microenvironment is a future trend in the early diagnosis and treatment of AP, but there are still many concerns that have led to the fact that nanomaterials are not yet widely used in the clinic, and one of the most important issue is the biosafety of nanomaterials. On the one hand, we still know little about the risks and their potential threats of nanomaterials, and the fact of lacking regulatory guidance and uniform standards for the toxicological assessment of nanomaterial-based drug delivery systems worsen this situation [137, 138]. On the other hand, most of the experiments conducted to date have been based on animal models, however, it is difficult for animal models to simulate the absorption, distribution, metabolism and excretion of nanomaterials in the human body as well as their effects on organs and tissues due to the complexity of the human immune system in terms of drug metabolism. Moreover, there are many common methods to establish AP models [97, 99, 107], and forms of AP caused by various different factors have their own specific characteristics. Researchers need to know the pathophysiology and limitations of each model in order to choose the appropriate model according to their own experimental needs. The technology for preparing AP models is not fully mature, and it is difficult for animal models to simulate the pathogenesis of human AP due to the diversity and complexity of its causes. Therefore, it is necessary to establish a unified scientific evaluation system, improve animal models, evaluation indexes and testing methods, and vigorously develop nanotoxicology, so as to promote the clinical translation of nanomaterials.

With the joint efforts of researchers in the future, multicenter and large-scale clinical trials can be realized. Additionally, with continuous technological development, artificial intelligence, big data analysis, 3D printing technology, and other fields have emerged, with which nanotechnology can be combined to generate new innovations and improve the ability to diagnose and treat human diseases, thus bringing a new era in the field of medicine.