Doxorubicin (DOX), a potent chemotherapeutic anthracycline antibiotic, is frequently used to manage numerous tumor types including breast and lung cancers [1]. Although DOX is considered as the golden standard to treat cancer, its administration is usually associated with adverse effects in off-target sites including; heart, kidneys and liver [2]. These toxic effects mainly arise from the over production of ROS during DOX's metabolism. Accumulation of ROS results in elevated oxidative stress, increased inflammation, leading to apoptosis and total cellular damage [3].

Phytochemical antioxidants exist in various vegetables and fruits and they play a master role in controlling ROS clearance [4]. Cinnamaldehyde (CNM) is a nutraceutical agent that belongs to the class of unsaturated aldehydes [5]. It is the main constitute of cinnamon essential oil with antimicrobial, anti-proliferative, hypoglycemic and antioxidant properties [6]. CNM has several drawbacks which hinders its clinical utilization as it is volatile, easily oxidized, highly reactive, and water insoluble [7].

Naringin (NAR), is a glycosidic polyphenol that is found in citrus fruits. It has numerous medicinal benefits including; anti-inflammatory, antioxidant, and anti -adipogenic properties [8]. However, NAR has limited clinical application due to its poor water solubility, instability in gastric pH and susceptibility to oxidation [9]. The antioxidant potential and ROS scavenging capacity of NAR is usually reduced in case of its oral administration due to its limited absorption and low bioavailability (7–8%) [10]. Encapsulation of NAR into nanocarriers can provide an effective option for improving its oral bioavailability, enhancing aqueous solubility, and achieving sustained drug delivery to the intestine [11].

Zein, is a prolamine protein derived from maize kernels which can be easily transformed into colloidal NPs having the capability to encapsulate small molecules and/or natural products by multiple techniques [12]. The anti-solvent precipitation method is the most utilized feasible technique as no expensive equipment, high temperature or high pressure are required to increase the dissolving rate of the hydrophobic protein or drugs [13]. Sodium casienate (NaCAS) is usually used as a cationic surface stabilizer to prevent aggregations of the prepared NPs via electrostatic interactions with anionic zein NPs [14].

Lactoferrin (LF) is a therapeutic glycoprotein that exists in mammalian, mucosal, and genital secretions. It has anticancer, antioxidant, antiviral, antibacterial, and anti-inflammatory effects [15]. LF can also be employed as a nanocarrier or active targeting molecule for efficient delivery of drugs to their desired sites depending on presence of LF receptors on the surface of numerous cells [16]. Furthermore, oral administration of drugs is the most comfortable and safe route for patients. Orally administrated drugs will be absorbed in the GIT to be bioavailable in plasma and then they will be transported via the bloodstream to target tissues in order to be therapeutically effective [17]. For stabilizing orally administrated nanoformulations, LF is frequently used as a coating molecule to improve drugs stability in gastric juice, and hence increasing their bioavailability and therapeutic effects [17].

The aim of this study is to utilize the privilege of LF's acid-resistant ability to coat casienate-coated zein NPs for gastric protection of encapsulated CNM and NAR. This dual coating strategy was found to increase the bioavailability of the encapsulated nutraceutical compounds, which in turn was found to improve their antioxidant activity and relieve the ROS produced due to DOX administration in an animal model.