Despite the fact that cancer therapy has progressed substantially in the last few decades, it is still a major cause of death around the globe. Conventional chemotherapy is the gold standard for treating cancer; however, it has limits due to dose constraints and consequential damage to healthy tissues [1,2]. Multi-drug resistance to chemotherapy is a critical problem in breast cancer, particularly at the metastatic stage when patients undergo multiple lines of treatment. Clinically, combination therapies are frequently used to circumvent chemoresistance [3]. A multi-pronged approach to overcoming drug resistance can achieve synergetic anticancer efficacy by delivering a cocktail of antitumor drugs or integrating chemotherapeutic agents with other traditional cancer treatments. Therefore, it is crucial to discover drug candidates with broad therapeutic effects, high efficiency, and minimal toxicity to effectively treat breast cancer [4,5].

Paclitaxel (PTX), the primary anticancer drug approved by US-Food and Drug Administration, exhibits antineoplastic activity, especially against various solid tumors. PTX inhibits cell replication and induces death by altering the dynamic balance within the microtubule system and prohibiting cells from entering the late G2 phase and M phase of the cell cycle [6]. Generally, 5-fluorouracil (5-FU) is an antineoplastic anti-metabolite pyrimidine-analog that typically induces a G1-S cell cycle arrest by inhibiting thymidylate synthase, an enzyme necessary for the conversion of deoxyuridylic acid to thymidylic acid in cancerous tumor cells [7]. 5-FU and PTX are intriguing strategies due to their distinctive mechanism of action, dearth of overlapping toxicities, and possible synergies. Numerous investigations have demonstrated that the fusion of PTX with 5-FU is an effective and well-tolerated method of treating various solid neoplasms, including primary or advanced breast carcinoma, drug-resistant ovarian malignancies, and recurrent stomach carcinoma [8]. Even though PTX and 5-FU are considered the first-line chemotherapeutics for patients with advanced breast cancer, combining the two may offer a cutting-edge approach to the disease's treatment [9]. Regardless of the limited effectiveness that has been evaluated so far, alternative, more efficient strategies are still required.

Owing to their distinct physicochemical features, metal oxide nanoparticles have gained a great deal of scientific interest in biomedical fields [10,11]. Among them, copper oxide (CuO) represents one of the most prevalent metal oxide nanoparticles. They are extraordinarily biocompatible and seldom toxic, which boosts their potential for usage in biomedicine [12,13]. Because of its versatility, it can be utilized as a carrier for chemotherapeutic drugs, mitigating the drawbacks of standard anticancer treatment. Its high surface-area-to-mass ratio allows it to store a substantial amount of drug molecules. Additionally, CuO's high ROS production ability and increased oxidative stress damage cellular DNA and impede cancer cell development, making it an enticing agent for anticancer therapy [14]. However, several studies have highlighted CuO NP's toxicity. We hypothesize that encapsulating CuO NPs in a polymeric carrier could be an effective strategy for addressing the toxicity concern [15].

Recently, the application of biodegradable nanomaterials is gaining more popularity. Poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), a sustainable biopolymer with such a low glass transition temperature and a rigid surface, is generated by employing starch as a feedstock and fermented bioengineering [16]. PHBV has numerous benefits, including its low production cost, toxicity, biodegradability, and non-toxicity. Unlike poly (lactic-co-glycolic acid) (PLGA), it does not disintegrate into acidic by-products that might damage human tissues, and it has a longer entrapment duration to avoid drug loss. Therefore, it is an appropriate biomaterial for use in drug delivery systems for the controlled release of chemotherapeutics [17]. Unfortunately, PHBV NPs lack the specific functional groups on their surface for direct coupling with targeting moieties. Thus, polydopamine (PDA) emerged as a reliable, simple, and ubiquitous surface coating material on a variety of substrates as a result of bioinspiration from the vital adhesion feature of invertebrate mussels, realizing a significant advancement in the surface functionalization of materials [18,19]. Catechol, the precursor to dopamine, is oxidized to quinone in a weakly alkaline environment (pH 8–8.5), where it subsequently combines with other catechol's or quinones to produce polymer films. As a result of the polydopamine (PDA) modification, the NP surface can covalently attach functional ligands such as peptides, antibodies, nucleic acids, and vitamins [20,21].

Target specificity is the most essential factor to consider when developing a tool for the delivery of anticancer drugs. Thus, to boost selectivity to the target cancer cells while leaving healthy cells unaffected, the surface of the nanocarrier can be decorated with particular target molecules (e.g., biotin, folate, or cRGD tripeptide) [22]. Among all three targeting molecules, folic acid plays an essential role in tumor cells. Folic acid promotes the uptake of nanoparticles into cancer cells, including cervical, breast, ovarian, and lung cancer, through a receptor-mediated endocytosis process [23]. Targeting modifications can improve therapeutic efficacy and lessen adverse effects, including non-specific toxicity, on healthy and targeted cells. Conjugated nano-carriers that specifically target tumor cells could selectively deliver their cargo to the tumor tissues while leaving the healthy cells unattended [24,25].

Therefore, in this work, to address the aforementioned issues, a dual drug-loaded metal oxide-based robust polymeric nanoplatform was prepared for enhanced cancer chemotherapy. The nanoplatform 5-FU@PTX-CuO@PHBV@PDA/FA was fabricated by loading chemotherapeutic drugs (5-FU and PTX) onto the surfaces of CuO NPs, which were then wrapped in a layer of PHBV, encased in PDA polymer, and finally anchored with folate molecules, which can target and kill cancer cells by Cu2+ therapy and chemotherapy. Here, PHBV is used to improve the encapsulation efficiency. At the same time, PDA is employed to trigger apoptosis through pH-responsive drug release in acidic tumor endosomes, and the CuO core can be utilized as a drug delivery nanocarrier and ROS-responsive tumor cell killing agent. Due to the surface modification of the targeted molecule FA, the 5-FU@PTX-CuO@PHBV@PDA/FA nanoplatform could be internalized through the FA receptor and released when exposed to pH stimuli. The diagrammatic presentation of the fabrication process of the dual drug-loaded DDS, 5-FU@PTX-CuO@PHBV@PDA/FA, is illustrated in Scheme 1. Physico-chemical approaches, including Ultraviolet–visible spectroscopy, Fourier transform-infrared spectroscopy, X-ray diffraction, Field emission scanning electron microscopy, and Transmission electron microscopy, were deployed to analyze and characterize the prepared nanoplatform. Subsequently, the anticancer activity of the multipronged 5-FU@PTX-CuO@PHBV@PDA/FA nanoparticles was assessed against drug-resistant MCF-7 breast carcinoma cells. In vitro investigations further demonstrated that the multifunctional nanomedicine exhibited substantial tumor inhibition qualitatively and quantitatively. Overall, the construction of the 5-FU@PTX-CuO@PHBV@PDA/FA therapeutic nanoplatform offered a realistic, cost-effective, biocompatible alternative for clinical targeted therapy against breast cancer.