Oral chemotherapy is the most potential therapeutic mode due to its convenience [1,2], while the mucus barrier, intestinal p-gp efflux and hepatic metabolism significantly limited the oral chemotherapy in clinic [[3], [4], [5]]. Nanomaterials with a size less than 1000 nm can pass through the intestinal biological barriers. Therefore, nano-encapsulation of chemotherapy drugs can protect them from adverse biological and physicochemical conditions in the gastrointestinal tract. A variety of polyester nano-preparations, including polymeric micelles [6], liposomes [7], and albumin nanoparticles (NPs) [8], have been used to improve the solubility, membrane permeability, and stability of chemotherapy drugs. However, the polymer material and drugs in these artificial NPs were generally loaded through non-covalent interactions, which was weak and led to low drug loading, unstable storage in vitro, premature drug leakage and rapid clearance during circulation in vivo [[9], [10], [11], [12]]. In addition, excessive polymer material caused the undesirable immune responses and polymer-related toxicity [13]. Cell-released bionanoparticles, extracellular vesicles (EVs), were a novel drug carrier with good biocompatibility, appropriate size distribution, flexible structural modifications, low immunogenicity, high membrane permeability, and inherent targeting. Thus, they can be used to improve oral absorption of chemotherapy drugs [14,15]. However, the EVs secreted by cells were difficult to mass produce and the drug loading could not meet the clinical needs, thus preventing them translating into clinical practice [15]. Recently, carrier-free NPs, which were composed of self-assembly or co-assembly of pure drug molecules or therapeutic components, have received considerable attention. Without any chemical modification, drug molecules can spontaneously form stable NPs through nano-precipitation. The drug in NPs had both carrier and drug identity, so it showed a high drug loading (60–100 %). And the simple nano-technology was helpful to eliminate the bottlenecks of quality control, expanded production and clinical transformation. To data, carrier-free co-assembed NPs were widely used for the delivery of chemotherapy drugs [[16], [17], [18]], but their application in oral drug delivery has not been reported. Although carrier-free co-assembled NPs have obvious advantages in improving the drug loading capacity, the removal by mucus layer, p-gp efflux, and the hepatic metabolism limited their application in oral drug delivery. Therefore, it was a challenge to ensure the high drug loading and the oral bioavailability of carrier-free co-assembled NPs.

Tannic acid (TA) was a kind of polyphenols widely distributed in plants, which has been approved by FDA as a food additive for food industry [19,20]. TA can also increase the drug solubility, so it was used for oral delivery of chemotherapy drugs of paclitaxel and curcumin [21]. Due to a lot of phenolic hydroxyl groups, TA was a good hydrogen bond donor, which can interact with BSA through hydrogen bonds to form microcapsules for delivering hydrophobic drugs [22,23]. Therefore, we proposed that TA can be adsorbed to mucin in intestinal epithelial mucus, so it can be used as an adhesive material for oral delivery of chemotherapy drugs.

In this study, a carrier-free co-assembled nanoplatform of piperine-TA-curcumin was synthesized by one-step nano-precipitation method. In NPs, piperine (Pip) was a traditional Chinese medicine monomer with significantly anti-tumor activity [[24], [25]], curcumin (Cur) was a p-gp modulator and a liver drug enzyme inhibitor [26] and TA was an adhesive material. DSPE-PEG2000 and PVP were used as stabilizers to adjust the stability of NPs (Scheme 1). We hoped to maximize the oral bioavailability of model drugs by simultaneously optimizing drug loading, membrane permeability and metabolic stability. We conducted a series of experiments in vitro, including adhesion tests, p-gp and liver drug enzyme inhibition experiments, to evaluate the effect of carrier-free co-assembled NPs. Also, cellular uptake, cytotoxicity and pharmacokinetics were performed to evaluate the delivery capacity of NPs and antitumor effect. This research provided a simple and effective strategy for oral chemotherapy drug delivery.