Cancer, characterized by the uncontrolled proliferation of cells, remains a formidable global health challenge and ranks as the second most common cause of death worldwide[1]. Liver cancer, in particular, has emerged as a significant contributor to cancer-related fatalities in 46 nations, with projections indicating a staggering 55% increase in new cases by 2040[2,3]. In the pursuit of effective cancer treatments, there is an increasing focus on natural compounds, mainly naturally occurring polyphenolic compounds. This heightened attention stems from the concerns surrounding the toxicity commonly associated with synthetic drugs utilized in cancer treatment[4,5].

Gallic acid (GA) and quercetin (QR), polyphenols derived from natural sources, have garnered significant attention as prospective nutritional supplements in the field of cancer therapy[6]. GA has demonstrated notable anticancer effects in different cancer cell lines. It effectively inhibits cell proliferation, induces apoptosis, and provides protection against oxidative damage without harming normal cells. In the context of cancer therapy, GA has been observed to impact all three significant mechanisms of cell death, namely apoptosis, ferroptosis, and necroptosis. This multifaceted influence on cell death pathways highlights the potential of GA as a versatile therapeutic agent for cancer treatment[7].

Similarly, QR showcases both antioxidant and anticancer properties, exerting its effects via different mechanisms, including apoptosis induction, antioxidant activity, and inhibition of angiogenesis and tumor metastasis. To enhance the targeted delivery and therapeutic potential of GA and QR, graphene oxide (GO) as pH-sensitive nanocarriers have been implemented[8,9]. GO facilitates the efficient encapsulation of these compounds, enabling targeted drug delivery, controlled release, prolonged circulation in the bloodstream, improved bioavailability, and reduced adverse effects. This approach reduces the need for frequent injections, mitigates systemic side effects, and maximizes therapeutic benefits[8,9].

Previous studies have conducted investigations into the encapsulation of QR within diverse graphene nanocomposite hydrogels, utilizing synthetic polymers such as hyperbranched polyglycerol (HPG)[10], polyetheramine (PEA) [11], polyvinylpyrrolidone (PVP) [12,13], and poly(2-(diisopropylaminoethylmethacrylate)) (PDPA)[14]. Similarly, GA has been incorporated into different functional GO-based nanomaterials, namely GO, reduced GO (rGO), and GO nanosheets (GONS), in order to augment its targeting capabilities against specific cancer cells[[15], [16], [17], [18]].

To enhance the biocompatibility of GO[24] and decrease its aggregation, it has been inserted into a hydrogel matrix, utilizing noncovalent interactions with biocompatible biopolymers, including chitosan (CS) or its derivatives[[19], [20], [21], [22], [23]]. The hydrogel matrix improves the dispersion and stability of GO, enabling a high drug-loading capacity and controlled release[25]. Furthermore, the hydrogel matrix enhances the interactions between the nanocomposites and biological tissues, thereby augmenting their efficacy[[26], [27], [28]]. CS assumes a pivotal role in alleviating the hemolytic properties of GO by establishing electrostatic interactions with red blood cells (RBCs)[29,30].

In this study, a biocompatible targeted delivery system utilizing GO/carboxymethylated chitosan (GO/CMCh) nanocarriers loaded with QR (QR@GO/CMCh) and GA (GA@GO/CMCh) was developed. The effectiveness of these novel nanocomposites was evaluated in delivering the loaded drugs and their impact on cell viability, targeting efficiency, and their biocompatibility with blood components. The significance of this work lies in the potential of these advanced nanocomposites to revolutionize drug delivery strategies, offering improved therapeutic outcomes and reduced adverse effects in biomedical applications.