During passive targeting, biomaterials-based nanocarriers generally act via physical and chemical interactions (hydrophobic and electrostatic interactions) as well as physical factors (such as carrier size and mass) to achieve targeted drug delivery (Attia et al., 2019). For pancreatitis, passive targeting can be achieved through increased permeability of tissue space and other microenvironment biochemical properties, including pH, reactive oxygen species (ROS), and digestive enzymes (Chiorean and Coveler, 2015).

Inflammatory responses can increase the permeability of blood vessels, subsequently triggering the extravasation through leaky vasculature and inflammatory cell-mediated sequestration (ELVIS) (Gong et al., 2019), which allows passive targeting of suitable size range nanoparticles for accumulation at the inflammation sites (Ren et al., 2019). Yao et al. (2020) developed silk-fibrin (SF)-based nanoparticles encapsulating bilirubin, the main anti-oxidant component of heme catabolism, for AP treatment. The animal experiment showed that the synthesized nanoparticles could selectively target the inflammatory sites in the pancreas to release bilirubin. The bilirubin-loaded SF nanoparticles prevented the NF-κB pathway and activated the Nrf2/HO-1 pathway to inhibit oxidative stress and inflammatory responses. In another study, L-α-phosphatidylcholine and cholesterol were mainly used to prepare nanoliposomes by thin layer evaporation technique (Shahin et al., 2022), loaded with caffeic acid phenethyl ester (CAPE) for oral administration in a rat model. The CAPE-loaded nanoliposomes decreased pancreatic secretions, oxidative stress, local inflammation, tissue apoptosis, and impaired energy status as therapeutic effects for AP treatment. The in vivo biodistribution study of the nanoliposomes was not performed; thus, the targeting effects could not be supported directly. However, the enhanced treatment efficacy was attributed to the altering tissue biodistribution of smaller-size liposomes and cellular uptake mechanisms (Shahin et al., 2022). Notably, liposomes particle size is their most influential characteristic affecting the circulation time and biodistribution after intravenous injection, which plays a vital role in passing through the leaky vasculature and accumulation at inflammatory sites in vivo (Ren et al., 2019). Anchi et al. (2018) synthesized curcumin-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles and evaluated the treatment efficacy in a cerulein induced AP model. The nanoparticles delivered curcumin to the inflammatory pancreatic site mediated by the ELVIS effect, resulting in a significant reduction of serum amylase and lipase levels, oxidative and nitrosative stress, and the expression of inflammatory cytokines. In addition, other previous studies have also reported the passive targeting of biomaterials-based nanocarriers via the ELVIS effect for AP therapy. Li et al. (2022) reported empagliflozin (EMP) loaded rebaudioside A (RA) micelles with a particle size of 5.234 ± 0.311 nm. The small particle size of the synthesized RA-EMP micelles (less than 20 nm) could benefit their cellular uptake and tissue accumulation for therapeutic effects against AP in a rat model by suppressing oxidative stress and proinflammatory cytokines.

Biomaterials-based nanoparticles with small size triggering the ELVIS effect at inflammatory sites have been applied in drug delivery and treatment of various inflammatory diseases. However, traditional nanoparticles are easily recognized by the reticuloendothelial system in vivo and are difficult to accumulate passively at the inflammation area via the ELVIS effect. For example, although the small particle size of RA-EMP micelles aided the passive targeting of EMP at the pancreatic inflammation site, the biodistribution study showed the highest EMP concentrations in kidney and liver tissues with reduced EMP accumulation in the pancreas, which could restrict the therapeutic efficacy (Li et al., 2022). Natural cell-membrane-modified nanoparticles have immense advantages in disease diagnosis and treatment due to the unique proteins, peptides, and enzymes present on the surface of cell membranes (Hwang et al., 2015) and are highly biocompatible to achieve extended circulation ability and/or target effects. Additionally, nanoparticles modified by partial or complete cell membranes can acquire the cell-derived bioactive property and homing effect for targeted drug delivery. Till now, membranes of various cell types, including red blood cells (Hu et al., 2011), platelets (Hu et al., 2015), white blood cells (Parodi et al., 2013), cancer cells (Chen et al., 2016), stem cells (Bose et al., 2018), etc., have been applied to modify nanoparticles for disease diagnosis and treatment. Utilizing the natural homing effect of cell membranes, nanoparticles can target the corresponding lesions to increase the therapeutic efficacy; the targeted homing effect is termed Bionic targeting (Liu et al., 2023). AP is an acute inflammatory disease characterized by the infiltration of a large number of inflammatory cells, including neutrophils and macrophages (Mayerle et al., 2012). Neutrophils are the most abundant type of granulocytes, accounting for 40 to 70 percent of all human white blood cells and the host’s first line of defense against invading pathogens and infections. The inherently phagocytic neutrophils can be activated by cytokines which then arrive at the inflammation sites (Selders et al., 2017; Castanheira and Kubes, 2019). Zhou et al. (2019) studied the treatment efficacy and mechanism of celastrol-loaded poly (ethylene glycol) methyl ether-block-PLGA (PEG-PLGA) nanoparticles coated with neutrophil membrane towards AP. The neutrophil membrane-modified nanoparticles aimed to endorse the Bionic targeting effect at the inflammation site through cytokines recruitment. In addition, the size of the applied nanoparticles (156.8 ± 2.3 nm) attributed to the passive ELVIS targeting effect. Furthermore, the modified celastrol-loaded nanoparticles reduced serum amylase levels and pro-inflammatory cytokines and inhibited systematic side effects in a sodium taurocholate-induced AP rat model.

The pH-responsive materials are usually capable of physical or chemical changes within a specific pH range (Lu et al., 2014). The pH-sensitive nanomaterials can achieve responsive release of drugs at the inflammatory site and correspondingly increase the drug accumulation (Kellum et al., 2004). Enhanced cellular metabolic activity leads to anaerobic glycolysis and lactic acid formation at the inflammation site (Zhang et al., 2020), resulting in an acidic microenvironment within the damaged pancreatic tissue. Applying pH-sensitive biomaterials to achieve passive targeting at the pancreatic tissues may further enhance the anti-oxidative and anti-inflammatory therapeutic effects. Silica nanoparticles, possessing porous structures and good biocompatibility, are usually used as carriers that can release drugs mediated by pH control to obtain their high concentrations within targeted tissues (Li et al., 2017; Zhang et al., 2018). Mei et al. (2020) developed silica-based nanoparticles encapsulating chitosan oligosaccharides (COSs) for their (COSs) targeted delivery to the pancreas, exerting anti-oxidation and anti-inflammation effects by activating Nrf2 and suppressing NF-κB and NLRP3 inflammasome for ameliorating AP. Moreover, the small size of the nanoparticles (305 nm) could also contribute to the ELVIS targeting effect.

The normal physiological ROS levels play an essential role in cell differentiation, proliferation, and migration (Hajam et al., 2022). In AP conditions, ROS are excessively produced in activated neutrophil and macrophage organelles such as mitochondria and endoplasmic reticulum. Overproduction of ROS can promote the production of inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin (IL) 1β, and IL 6, accelerating the progression of AP (Carrasco et al., 2014). The nanocomposites sensitive to oxidative response can be utilized in targeted therapy for AP. For example, intraperitoneal administration of yttrium oxide (Y₂O₃) nanoparticles decreased oxidative stress and attenuated the mitochondrial stress and inflammatory markers in an AP rat model (Khurana et al., 2019). The Y₂O₃ nanoparticles, like catalase and superoxide dismutase mimetic, possess promising anti-oxidation properties (Heckert et al., 2008).

During the trigger and development of AP, a variety of enzymes can be secreted by pancreatic tissues, such as proteolytic enzymes (Hu et al., 2020) and phospholipase A2 (PLA2) (Friess et al., 2001). Biomaterials-based nanoagents with enzyme response properties can achieve passive targeting effects at inflammatory sites to improve therapeutic mechanisms for AP. As discussed above, the SF protein in bilirubin-loaded SF nanoparticles, which induced the ELVIS passive targeting effects towards inflammatory pancreatic tissues (Yao et al., 2020), can be degraded by proteolytic enzymes, making SF a candidate material for enzyme-responsive nanoagents design (Zhao et al., 2015). As a result, the bilirubin-loaded SF nanoparticles also exhibited enzyme-responsive targeting effects for enhanced inhibition of oxidative stress and inflammatory responses (Yao et al., 2020). In another study, neutrophil membrane-coated SF-nanoparticles encapsulated with ferulic acid (FA) were developed for in vivo targeted delivery of FA to inflammatory pancreas lesions showing anti-inflammation and anti-oxidation effects (Hassanzadeh et al., 2021). The major components of the nanoparticles, SF and the entrapped neutrophil membrane, endowed the nanoagent with enzyme-responsive and Bionic targeting effects, respectively. Additionally, FA is a phenolic compound that has been applied in the treatment of various diseases, especially those accompanied by severe oxidative stress and inflammation responses (Zdunska et al., 2018). Zhang et al. (2021) synthesized macrophage (MΦ) membrane-coated PLGA nanoparticles modified with melittin and MJ-33 for AP treatment. Melittin is a short peptide with a high affinity for PLA2, while MJ-33 serves as a PLA2 inhibitor. The MΦ membrane and melittin in the nanocomposite may benefit the Bionic and enzyme-responsive targeting effects, respectively. In a rat AP model, these nanoparticles suppressed PLA2 activity, thus, preventing inflammatory responses and decreasing pancreatic tissue damage.

Passive targeting based on the ELVIS effect and other mechanisms is insufficient due to the non-specific reaction between cells and nanoagents, leading to a significant reduction in cellular endocytosis of nanoagents. This affects the bioavailability of drugs and their therapeutic effects, resulting in drug leakage and resistance in the organism (Lee et al., 2022). To overcome these limitations, biomaterials-based agents with active targeting properties should be considered; specific ligands or non-serum based-biomarkers can be applied to increase the treatment efficacy of AP. The nanoparticles modified with specific peptides can recognize and bind with corresponding receptors expressed in certain cells in the inflammatory sites, resulting in enhanced drug accumulation (Da Silva-Candal et al., 2019; Lin et al., 2021). Hung et al. (2021) selected five pancreatitis-specific peptides using a computational-guided in vivo phage display approach, demonstrating selectivity to different pancreatic cells. The peptide-conjugated liposomes were encapsulated with apigenin for the targeted delivery of the drug to inflammatory pancreatic tissues for acinar cell preservation and oxidative stress reduction. Despite the advantages, the active targeting property of biomaterials-based nanoagents has not been studied and exploited extensively for AP treatment, highlighting the need for further research in this area.