Targeting Breast Cancer Signaling via Phytomedicine and Nanomedicine

Recent breakthroughs in treating cancer, which is a primary cause of illness and death globally, have only had a minor impact on individual survivability. Investigators seeking to create potential anticancer medicines are increasingly interested in the factors influencing cancer performance and sustainability [1‒8]. Inflammation’s role in influencing cancer development has been underlined recently [9]. Inflammation has been linked to each stage of tumor formation, particularly onset, progression, metastasis, and relapse. Extrinsic and intrinsic tumor inflammation, induced by autoimmunity, infectious diseases, or other variables contributing to cancer and speeding up neoplastic progressions, such as obesity, smoking, and alcohol intake, invoke genetic changes or provide a favored context for tumorigenesis. Inflammation governs cancer growth and might have a negative impact on therapeutic results [10, 11]. Treatment-induced inflammation only develops after treatment but may be crucial in determining drug efficacy or resistance [12]. Cancer and immune cells communicate actively or passively via chemokine and cytokine. Inflammation’s pro-tumorigenic impacts are frequently regulated through feed-forward cycles in signaling pathways.

Nanomedicine utilizes nanosized tools, while phytomedicine utilizes phytoconstituents to treat disease and improve quality of life. The nanomedicine and phytomedicine approaches are nowadays focused because the presently available chemotherapy’s main drawbacks are tumor regrowth, resistance, and harmful effects on non-targeted cells, which might limit the use of antitumor medications and hence lower the quality of life for patients. Plant-based phytonutrients (phytomedicines) and analogs can potentially amend therapeutic utility and shorten complications in cancer patients. Several phytonutrients are physiologically active substances found in nature with high anticancer activities [13]. Nanomedicine and phytomedicine ensure effective chemotherapeutic medicines with improved efficacy and fewer side effects persist in facing the obstacles of current therapy. Cancer nanotechnology has become an innovative and potentially adjunctive therapeutic approach because of the gaps in traditional cancer treatments. It offers new possibilities for early recognition, improved therapy, prognosis, and an effective cancer diagnosis. The emerging interest in using nanotechnology for cancer control is mainly due to the therapeutic potential of certain nanostructures and the distinguishing structural characteristics of cancer. Although cancer nanotechnologies have the potential to administer dose-specific chemotherapeutics (with little toxicity), it is crucial to take into account the intricacy and kinetics of the tumor to bridge the translational bench-to-bedside divide [14, 15]. Several nanomaterials were used to discover and advance existing cancer therapies. Highlighting the determinants of inflammation in multiple stages of tumor emergence will aid in developing theranostic strategies that utilize inflammatory processes and preferentially attack the tumor-associated environments [16]. Several ways are employed to amend cancer chemotherapies’ performance while reducing their toxicities. Tumor diversity can result in poor therapeutic effects, developed resistance, and unwanted side effects.

Nonetheless, employing nanomedicines to address and modulate the tumor microenvironment is essential for improving cancer’s therapy effects [17]. Nanomedicine is primarily used as a carrier system for immunoregulatory drugs, allowing for faster and more targeted delivery of these agents to aid in mounting anticancer immune function [18]. The history of nanomedicine and phytomedicine can be traced back to ancient times [19]. In modern times, pioneers of nanomedicine, Metchnikov and Ehrlich, Nobel Prize for Medicine winners 1908, worked on nanomedicine as therapeutics and diagnostics [20]. The research on nanomedicine and phytomedicine has increased dramatically in the last 30 years of the 20th century [19]. The role of nanoparticles (NPs) in biomedicine appeared in the 1970s, and since then, around 10,000 research papers have been published [19]. In this review, we looked deeper into the role of natural products, mainly nanomedicines and phytomedicines, in cancer treatment by focusing on various inflammatory signaling pathways (Table 1, 2).

Formerly, most cancer treatments used pharmacological drugs, surgical intervention, or radiotherapy to destroy or eradicate tumor cells surgically. Then it progressed to therapeutic strategies, with the development of medications targeting molecular mechanisms, including specific kinase inhibitors and monoclonal antibodies. These treatments dramatically refined cancer patients’ well-being and longevity. The effectiveness and safety concerns continued to restrict cancer therapies’ full potential. Nanomedicine provides a more precise targeting method for these medicines, allowing them to improve drug accumulation in tumors while minimizing systemic toxicity.

Moreover, nanomedicine was developed to solve a number of problems with conventional cancer therapy, such as the lack of cooperation of free medicines and the establishment of chemoresistance [34, 35]. Most biologically active constituents are highly soluble in water but have low absorption because they cannot cross the lipid membranes of the cells, have excessively large molecular sizes, or are poorly absorbed, resulting in a loss of bioavailability and efficacy. Such circumstances make phytomedicines unavailable in clinical settings. Some extracts are not used clinically because of these obstacles [36]. Combining natural products with nanotechnology has been a promising approach. The nano-structured systems allow the biologically active constituents to potentiate the pharmacological action by reducing the dose and side effects and improving activity. Using nano-based formulations in plant medicine research has several benefits, such as increased solubility and bioavailability, dispersion of tissue macrophages, and therapeutic properties. Nano-formulations also offer protection from toxicity, stability, and long-term administration. Emergent formulations like niosomes, liposomes, nanospheres, and phytosomes are feasible options as carrier molecules for the efficient delivery of drugs in clinical settings. Anti-inflammatory medicines have been used as a treatment strategy because of the involvement of inflammation in cancer formation and recurrence. The transport of anti-inflammatory medicaments to malignant cells is the greatest obstacle. Nanotechnology has made specialized cancer therapy both safe and effective.

However, the speed of nanomedicine development has been hindered by the complicated and varied characteristics of cancer, limited evidence on the outcome and behavior of nanomedicines in the patient’s psyche, and a lack of large-scale commercialization. A complete grasp of the tactics, developments, success, problems, and future views is required to transform the narrative from traditional cancer therapies to anti-inflammatory nanotherapeutics [37]. Tumor resistance is assisted by several signaling pathways, notably PI3K/AKT/mTOR, RAS, WNT/β-catenin, TGF-β, and notch. The adaptable inflammatory action is the body’s frontline of infection defense. NF-κB, MAPK, JAK-STAT, and PI3K/AKT are cancer’s most typically dysfunctional inflammatory mechanisms. Nanomedicine, as a platform for transporting therapeutic medicines that selectively target tumor locations, is getting popular as an attempt to alleviate major obstacles in treating cancer. Polymer and INPs, liposomes, micellar nanostructures, nanotubes, and exosomes have all been widely researched as sustainable nanostructures. Because of their toxicity, sensitivity, and quick clearance by the mononuclear phagocytes, exosomes have been identified as a promising prospective method for the bioinspired, biologically engineered, and biomimetic delivery of drugs [38].

Addressing these inflammatory pathways has been demonstrated in preclinical research to effectively suppress tumorigenesis and metastasis, suggesting that they could be useful therapeutic strategies for individuals with inflammation-related breast cancer (BC). Additional biological processes observed in inflammatory BC include suppressing the TGF-β pathway and genetic changes in proteins that regulate cell growth. More research is needed to establish its physiological activity and therapeutic roles in inflammatory BC. Therapies that target the EGFR and JAK2 pathways are likely the first and most established in terms of clinical application [39].

Attaching ligands to the NP’s surface allows them to validate and bind specifically to corresponding molecular markers on the surface of specific BC cells, making them ideal for addressing BC cells. The ligand-NP conjugation interacts with BC receptors (e.g., HER2, EGFR, VEGFR, IGF-IR), induces NP internalization via endocytosis, and transfers the linked proteins to the active areas of tumor cells via proteolytic cleavage [40]. In progressed aggressive tumors and most malignancies, enhanced amplification of systemic inflammation has been found. Radiotherapy and chemotherapy cause a high tumor-associated inflammatory process. Due to chemotherapy’s inability to identify between tumor and normal cells, emphasis has been placed recently on producing targeted medicines with greater precision for cancerous cells, greater efficacy, and reduced toxicity [41]. Small-molecule inhibitors (SMIs), organic biomolecules, composite cytokines, local irradiation, neutralizing antibodies, oncolytic viruses, Toll-like receptor agonists, and specialized pro-resolving lipid mediators are all investigated as ways to attenuate inflammatory response in cancer treatment (Fig. 1).

Polymer-drug conjugates, including NPs in association with certain other SMIs, phytoconstituents, and siRNA, have been the most dominant groups of targeted therapies in cancer treatment due to breakthroughs in nanotechnology. NPs are employed to incorporate active chemicals for better delivery systems in various cancer therapeutic strategies. By controlling mTOR activity, NPs could halt cellular proliferation in tumor cells [42]. Polyamidoamine, a type of nanocomposite designed for clinical use, disrupts the AKT-TSC2-mTOR signaling cascade, resulting in autophagy [43]. SiO₂NP suppresses the PI3K-AKT-mTOR signaling cascade by repealing the NO-NOS system, generating an inflammatory response in tumor cells that results in apoptosis [44].

Song et al. [45] developed hyaluronic acid (HA)-coated, mannan-conjugated MnO₂ NPs (Man-HA-MnO₂) to modify multidrug resistance by utilizing HA’s potential to remodel anti-inflammatory, pro-tumor M2 TAMs (tumor-associated macrophages M2) to pro-inflammatory, antitumor M1 macrophages. In a breast tumor mouse model, therapy with Man-HA-MnO₂ particles boosted tumor oxygenation while downregulating HIF-1α (hypoxia-inducible factor-1) and VEGF. Compared to chemotherapy alone, combining these NPs with doxorubicin (DOX) suppressed tumor development. Zuo et al. synthesized cationic lipid-aided polymeric NPs enclosed with siRNA to create a suitable siRNA delivery method for anti-breast cancer stem-cell (BCSC) therapy. The BCSCs were then effectively removed in vitro using NPs supplied with siRNA addressing the oncogene Plk1. They blocked the TGF-β type I receptor and TGF-β signaling, allowing NPs to penetrate tumor tissue more easily (Fig. 1). The tumor microenvironment (TME) was changed, and the enhanced penetration and retention impact was modified [46].

The tumor targeting with drugs/phytopharmaceuticals utilizing various nanosized carriers like liposomes, NPs, polymers, micelles, and conjugates of NPs is the main focus of nanomedicine [47]. There are two ways through which nanomedicine work. One is by covalent drug attachment using linkers to the targeted receptor, which is required to be recognized by tumor cells and is called active targeting. The other is passive targeting, where the enhanced penetration and retention effect is utilized [19]. The main factors are stability and drug release rate until the targeted tumor cell. The bioavailability of the drugs in biological tissues and fluids is quantified using various imaging techniques like magnetic resonance (MRI), gamma cameras, near-infrared (NIR) luminescence, and fluorescence and positron emission tomography (PET) are major techniques. In active targeting where the drug attachment with the targeted receptor has been traced via in vitro but very less in vivo, the progress is very slow [19]. The targeted antibody-mediated radiotherapy demonstrated less than 0.01% of the dose administered at the tumor site [48]. The pharmacological evaluation must often be conducted via dose-dependent targeting and saturation of the targeted receptor, which occurs even at low doses. In several nanomedicine technologies, biomarker estimation becomes important to estimate the efficacy and toxicity of the drugs as only very few drugs reach clinical trials and market [49]. The new advancements in novel nanomaterials have attracted increased attention toward theranostics and nano-vectors in nanomedicine in the past 10 years.

The carbon base materials consist of single-wall and multi-wall carbon nanotubes, fullerene (mainly C₆₀), nanodiamond (ND), and graphene oxide (GO). However, all these materials are not soluble in water and can be solubilized by polyfunctionalized polyethylene glycol (PEG). Carbon cores are essentially used for scaffolds and cancer targeting; the Raman signatures have huge potential. The toxicity or safety concerns with these materials need to be addressed. Chronic use makes it an issue, although clinical investigation is a very important aspect [50, 51].

Gold nanoparticles (GNPs) have been brought to nanoscience through novel theranostic concepts based on the medium-sensitive plasmonic absorption leading to infrared light and visible light-induced collective oscillation of the electrons on the gold surface when the NP size is very tiny than the wavelength of light [52, 53]. The GNP plasmons can be useful to nanomedicine in several ways, like photo-thermal therapy [19, 52, 53]. GNPs provide versatile scaffolds for cell surface sensing using array-based “chemical nose” approaches and specific recognition. Passive cancer targeting with PEG and active cancer targeting with covalent bonds to rhTNFα (CYT-6091) have reached clinical trials [54]. The GNP is considered safer, more superior in terms of plasmonic properties than group 11 elements [19].

Despite the safety concerns, the superparamagnetic iron oxide NPs (SPIONPs) are widely used with magnets for cancer ablation by hyperthermia and MRI [55, 56]. These techniques have reached phase II for glioblastoma and prostate cancer [57]. Some other oxide NPs, like silica, encapsulate drug molecules for delivery [58]. The Quantum Dots (QD) NPs are widely applied in nanomedicine coated with ZnS/CdS for various applications, including cancer [19, 59].

The drug nano-vectors in nanomedicine have been studied extensively, including polymers, copolymers, antibodies, aptamers, proteins, and dendrimers [19, 58, 60]. Several biodegradable polymers are used in clinical studies [61]. The challenges in these polymers include poor drug loading, burst release, and poor miscibility with the drugs [62]. Dendrimers have a huge capacity to encapsulate drugs, and microbiocide Vivagel was investigated clinically [19]. The clinical investigations remain slow, although the major obstacles are reproducibility, purity, biocompatibility, and biodegradability [63].

The most successful in the nanomedicine remained are liposomes, as the anticancer drug carriers. The combination of drugs and imaging agents for diagnostics is the main example called theranostics [64]. The research on nanomedicine is expanding daily; however, there is a need for a multi-disciplinary approach between chemists, biophysicists, pharmacologists, clinicians, and biomedical engineers to produce nanoengineered drugs for the market.

Using NPs as drug delivery systems (DDS) is fraught with difficulties, including biodistribution, bioavailability, and potential toxicity. The use of PNPs in targeted DDS had modest results in translating preclinical methods to clinical trials for cancer treatment. Restricted ligand-receptor interaction, upregulation of surface markers on healthy and cancerous cells, the complexity of routing the therapeutics in notably minute doses to the tumor area, and NP buildup in non-targeted sites that result in nanotoxicity are some of the difficulties encountered during targeted DDS fabrication [65]. Another challenge in drug delivery is unwanted communication among biological entities and NPs, leading to unfavorable interactions and toxicity [66]. Nanocarriers’ physicochemical characteristics differ from batch to batch, and their substantial manufacture is likewise relatively challenging [67].

Nanomaterials for the delivery of drugs need to be precisely developed and evaluated to prevent nanocarrier toxicities in healthy cells. The protein crown, a biomolecule layer that surrounds NP complexes in biological contexts, oversees promoting the succeeding contacts of cells with the activated NPs. This protein crown interacts with the periventricular tissue’s surroundings, penetrates the tissue, and causes cells to internalize. By decreasing the adherence between NPs and the cell membrane, the protein corona ingestion on the NP’s surface renders the addressing capabilities of the naked NPs [68‒70]. Additionally, NPs cause protein aggregation, influencing their toxicity and targeting potential. The deposited proteins have a detrimental effect on the selectivity of NPs and help tumor cells activate mTOR, which causes cellular death [71, 72].

Clinical development will be facilitated by resolving the challenges of predictable, reproducible, and sustainable NP synthesis and NP detection and validation. Even though known pharmaceuticals have been utilized as the cargo in most approved NPs, we may anticipate that the next generation of nanomedicines will progressively include novel molecular domains and innovative therapeutics, including siRNA and mRNA genetic manipulation [15].

Nanomedicine has increased the potential for advancing BC treatment by enhancing the existing DDSs. Novel potential for upfront diagnosis and monitoring has been made possible by advancements in nanotechnology. We may better regulate the safety and usefulness of systemically delivered chemotherapeutics by adjusting the bioavailability of nanomedicines and their drug target aggregation [73]. Limited solubility, penetrability, rapid first-pass effect, and P-gp efflux are issues with the existing chemotherapeutics. Additionally, many chemotherapies can make cancer resistant. Therefore, the goal is to create an efficient therapy regimen using a nanomedicine method for BC treatment. The important discovery with the presently available therapy is that the drug, in addition to dispersing to the spot relevant to the target, also disperses to healthy tissue, resulting in significant toxicity. An alternative to the issues context of current chemotherapy treatments for BC is provided by nanomedicine. The nanomedicine techniques offer a target-specific medication employing several innovative drug delivery approaches, making them advantageous over the typical BC therapy [74]. Nanocarrier systems are being developed as a result of studies in the area of nanomedicine. These tactics involve functionalizing these nanostructures with functionalities that promote site-specific, customized drug release. Liposomes, nanogels, polymer micelles, and dendrimers are a few NP approaches that can overcome various biological obstacles in drug delivery.

The anticarcinogenic functions of phytochemicals, which control cellular processes like cell growth, cell death, migration, and invasion by attenuating various signaling pathways, are being supported by more and more investigation (Table 2). However, their diagnostic use is obstructed by poor hydrophilicity, poor absorption, destabilization, and biodegradability. Research has provided innovative formulations to increase the utilization of phytochemicals in anticancer therapy. Targeted delivery is made possible using nanostructures to extend the life span of phytochemicals in circulation and their bioavailability and durability [75]. Using nanoparticulate-based DDS in cancer treatment is promising because these naturally occurring nanosized substances have changed bioactivities and substantially reduced toxicity.

As previously mentioned, quercetin and its metabolites are essential in destroying malignant cells by focusing on inflammatory pathways. Quercetin-loaded Au nanoparticles (Qc-AuNPs) have been emphasized in reports using BC cell lines to effectively limit the epithelial-mesenchymal transition by blocking the transcription repressing agents, i.e., Snail, Slug, and Twist, and also angiogenesis and pervasiveness through the EGFR/VEGFR2-assisted pathway, and cycle arrest by impairing the EGFR/PI3K/AKT-assisted pathways [76]. AuNPs-Qu-5 has now been suggested as a promising medication delivery platform to treat BC and has been demonstrated to be more efficient in killing cancer cells than free quercetin. Resveratrol, 6-Gingerol, and other phytonutrients have also been coupled with nanomedicines to enhance their therapeutic value [75, 77].

SMIs are cancer therapy drugs to treat established, treatment-resistant malignancies and persistent invasive tumors. They include multitargeted and extremely targeted kinase inhibitors, DNA repair enzymes, epigenetic regulatory proteins, and proteasomes. C-MET and FLT3 inhibitors are two of the many receptor tyrosine kinase inhibitors that prevent tumor growth by concentrating on inflammatory signaling pathways. Several downstream signaling pathways, including PI3K/AKT, RAS/MAPK, FAK (focal adhesion kinase), STAT3/5, RAC/RHO, phospholipase Cg (PLC-g), SHP2, c-SRC, and CRKL, are activated when the C-MET receptor unites to its sole ligand, HGF (hepatocyte growth factor). These pathways govern viability, cell growth, invasion, and motility [78].

As crucial cytoplasmic kinases, often STKs, are activated when RTKs are activated, RTKs are a popular choice as a primary target for anticancer medications. The extracellular RTKs and cytoplasmic STKs are the targets of SMIs. Deregulated RTK activation promotes enhanced cell growth and survival, which frequently aids in cancer development. In particular, human epidermal growth factor receptor 2 (HER2), a member of the EGFR family of RTKs that is upregulated, is elevated and consequently highly expressed in some breast tumors. The phosphoinositol 3′-kinase/Akt route, the Ras/Raf/MAPK pathway, the STAT3 pathway, and the PLC-γ-CaMP pathway are only a few downstream signaling cascades stimulated by the activated tyrosine kinases [79, 80]. Chaperones, known as heat shock proteins (HSPs), aid in correctly folding and transporting proteins across the cell membrane. As they aid in the appropriate folding and transport of oncoproteins, which are crucial components of numerous signaling pathways, HSPs are linked to the growth and severity of cancer. It has been revealed that unusually higher levels of HSP27, 70, and 90 expressions are present in several malignancies, resulting in chemotherapy resistance and apoptotic inhibition. HSP90 is required for the oncogenic proteins HER2 and c-Src to function, which are essential for the development of BC. The new HSP90, SMI ganetespib, which has been demonstrated to have antitumor activities to combat several malignancies, is being researched as a potential cancer treatment [81‒83].

Fulvestrant, a specific estrogen receptor down-regulator, is an efficient endocrine therapeutic option for women with metastatic BC that is hormone-sensitive. It leads to the inhibition of BC cells. For the treatment of metastatic BC, fulvestrant has been approved. In metastatic hormone, receptor-positive BC cases that have persisted or reverted to past tamoxifen or aromatase inhibitor therapeutic processes, the coupling of fulvestrant with CDK4/6 inhibitors has demonstrated higher potency in the monotherapy process. Fulvestrant with alpelisib, an α-selective PI3K inhibitor, has been implemented for instances with PIK3CA mutant BC that has advanced on an endocrine treatment approach [84‒86].

Phytochemicals are significant chemopreventive agents that boost the production of antioxidants and the Nrf2-ARE (antioxidant-response-element) signaling pathway [87]. Phytoconstituents exhibit a variety of activities on numerous molecular targets in signaling pathways and alter the autophagy/apoptosis equilibrium, which controls cell viability. In addition to causing cell death in tumor cells, phytochemicals also cause necroptosis, which slows tumorigenesis and invasion [88‒90].

Flavonoids have antioxidant features and can alter signaling pathways, including MAPK/p38, PI3K/AKT, apoptotic processes, and Wnt, which eventually relates to their anticancer characteristics [91]. Curcumin is a polyphenol that modulates tumor cell proliferation and has received much interest in cancer therapies. It affects various cell signaling pathways, notably EGFR, erbB2 (erythroblastic oncogene-B), AKT, sonic hedgehog, Wnt/β-catenin, NF-κB, and STATs metastasis and angiogenesis [92, 93]. The primary molecules curcumin addresses to kill cancer cells are COX-2, NF-κB, TNFα, and cyclin D1. After curcumin therapies, cyclin D1 and CDK4 activation in breast and skin malignancies were greatly diminished in several in vitro investigations.

Additionally, curcumin inhibits the activity of activator protein-1 (AP-1), reducing the activation of angiogenic markers like VEGF, angiopoietin, MMP-9, and MMP-3 [94]. A flavonoid called apigenin has antiangiogenic characteristics by controlling signaling pathways, inducing apoptosis, preventing cancer cells from transforming, and arresting the cell cycle. The in vivo findings demonstrated that apigenin declined the production of Her2/neu protein and limited the PI3K/Akt/Forkhead box O-signaling cascade in BC mouse models [94‒96]. Table 3 lists small molecules and phytomedicines that aim at inflammatory pathways in BC therapy.

In BC stem cells, ginsenoside F2 had anti-proliferative properties and activated the autophagosome process. In addition, ginsenoside F2 attracted GFP-tagged LC3-II to autophagosomes, stimulated the production of acidic vasculature organelles, and increased Atg-7 expression [123]. Quinacrine improved the activation of p53 and p21 and inhibited topoisomerase activation in BC cells, exhibiting anticancer effects [124]. Juglanin, typically derived from green husks, also demonstrated anticancer action. By controlling the ROS/JNK signaling system, juglanin-mediated therapy reduced G2/M phase arrest and activated apoptosis in human BC [125].

The detection, management, and mitigation of BC are several applications for nanotechnology. Numerous nanostructures were designed with the specific purpose of attacking BC that has progressed. By lowering utilization and medical costs, two key barriers to traditional cancer treatment-targeted NPs, DDS aims to lessen the negative impacts of antitumor medications [126]. Several nanostructures were utilized as delivery carriers for medications and diagnostic agents. Liposomes, polymeric vehicles including microspheres, hydrogels, polymeric NPs, dendrimers, nanowires, metallic NPs (e.g., Au, Ag, Ti), carbon nanodevices (e.g., nanotubes, NDs, graphene), inorganic particles (e.g., silica particles), and hybrid nanostructures have all been used [127]. Several nanomedicine approaches for the treatment of BC are given in Table 4.

Cancer nanotechnology has emerged as a ground-breaking and potential adjuvant therapy approach due to the shortcomings of traditional cancer treatments. It offers new opportunities for early recognition, enhanced therapy, a better prognosis, and effective cancer diagnosis. The emerging interest in using nanotechnology to control and fight cancer is primarily due to the therapeutic potential of certain nanostructures and cancer’s distinctive structural characteristics. Although cancer nanotechnologies can potentially administer dose-specific chemotherapeutics (with little toxicity), it is crucial to consider the intricacy and kinetics of the tumor to bridge the translational bench-to-bedside divide [14, 15]. Due to the lack of clinically available nanocarriers that take advantage of a broad range of nanoscale properties, the prospect of nanotechnology in medicine remains unrealized. Although therapeutic agents (chemical, physiological, or nanotechnological) addressing a portion of cancer cell subsets in vitro and even in relevant animal studies have been shown to be very efficient and cell-selective, several have collapsed during human trials. Long-term efforts to improve the regional localization selectivity of therapeutic NPs by adding targeting components to them have not shown promising outcomes. This mistake is related to using molecular targeting agents to increase identification efficiency but at the expense of far more challenging obstacles to overcome when crossing biological barriers [136].

The outcome of aggressive tumors in cancer biology, like triple-negative BC and pancreatic cancer, can be significantly improved by nanomedicine. In treating triple-negative BC, novel methods, including hemodynamic targeting, have shown potential for combating drug resistance and targeted delivery. Moreover, it is crucial to remember that the absence of professional insight in large-scale clinical-grade operations makes monetization for cancer nanomedicines difficult. Small compounds and antibodies are produced with particular expertise in modern pharmaceutical manufacturing facilities [137]. However, despite overstating preclinical outcomes, scientific studies must continue to uncover nanomaterials and pinpoint innovative approaches to nanocomposite cancer therapy. It may even learn through nature’s delivery mechanisms. It is crucial to thoroughly comprehend the therapeutic efficacy of cancer nanomodalities by looking at their physical interconnections. Translational research must take a “disease-driven” strategy instead of a “formulation-driven” one to generate clinically significant cancer nanotechnology that assists people in the long run [136].

Currently, over 50% of necessary medications originate from nature. Because of its improved therapeutic effectiveness and fewer side effects relative to allopathic drugs, the usage of phytomedicine has grown over the past few years. Due to their limited hydrophilicity, lipophilicity, and improper molecular size, which leads to limited absorption, phytomedicines have demonstrated excellent in vitro activity but limited in vivo efficiency. Some of these issues can be addressed, and appropriate dosing regimens can be established with a deeper comprehension of the pharmacokinetics of phytomedicine. Using nano-based formulations in phytomedicine investigation has several benefits, such as increased solubility and bioavailability, increased therapeutic properties, protection from toxicity, increased tissue macrophage dispersion, better stability, sustained delivery, and protection from chemical and biological decay [138]. Using emerging formulations like niosomes, liposomes, nanospheres, and phytosomes is feasible. By reducing toxicity and boosting bioavailability, these DDSs could effectively lessen frequent dosing to combat non-compliance and improve therapeutic value. Therefore, incorporating NPs as DDS in the conventional medical system could aid in the fight against more severe diseases like cancer, diabetes, and asthma [36, 139].

The inflammation in cancer has a great influence on the plasticity TME. During carcinogenesis, inflammatory processes can be pro-tumorogenic/blocking antitumor immunity or anti-tumorigenic (immunosurveillance). The inflammatory process could exert signals that direct pro-tumorogenic signaling. The key role of inflammation in all stages of tumor growth calls for investigating the molecular events behind early tumorigenesis and propagation. The main goal of cancer therapy is to encourage the cancer-inhibiting inflammatory process and suppress cancer-promoting inflammation while maintaining a healthy alignment of inflammation, which is the most challenging treatment aspect. The cancer cells express the multidrug-resistant proteins to efflux out the anti-cancer drugs. The inflammation process is complex, and many reactions occur in TME. The inflammation has been proposed to alter MDR expression in cancer cells [140]. Various inflammatory mediators like chemokines, cytokines, and prostaglandins have been reported to regulate the expression of the MDR transporters in tumor cells. Such factors are crucial in the bioavailability of anticancer drugs at TME. It has been proposed that anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs and glucocorticoids enhance the therapeutic outcome and maintain the balance of bioavailability of anticancer drugs [140]. It is important to uncover all the mechanisms between MDR proteins and inflammation that will be helpful in the therapeutic management of cancer subjects with malignant cancers with high death rates.

In order to improve their pharmacokinetic profile and reduce the off-target impacts, medications must be delivered via substrates that restrict drug breakdown and transformation in the circulatory and phagocytic pathways. Numerous NPs, bioflavonoids, phytocompounds, and small molecules are used in different targeting approaches, mostly inhibiting the PI3K-AKT, MAPK, and STAT3 pathways. By preventing the formation of p53 and increasing the transcription of the anti-apoptotic proteins (Bcl-2 and Bcl-xL), NF-κB and STAT3 both show good tumor-promoting processes. Most drugs block migration, penetration, and adherence to cancer cells while activating Bax proteins to cause cell death. It is necessary to research to develop low-toxicity anti-inflammatory drug combinations that can address inflammation-related signaling pathways in BCs with various phenotypic characteristics. The bioavailability problems posed by several elements, including the utilization of nanocarriers, liposomes, prosthetic polymeric micelles, phospholipid-based drug carriers, and microspheres, have recently been postulated to tackle these consequences and call for specialized investigations. Implementing any custom strategy that accents the goal of these signaling pathways to lessen toxicity and broaden the range of host defense to display profound importance for anticancer activity must be done with caution as we work to solve the challenges of conventional chemotherapies.

The authors have no conflicts of interest to declare.

No funding was received to carry out this study.

Writing original draft: Jeba Ajgar Ansari and Sakeel Ahmed; conceptualization, review and edit, and writing original draft: Jonaid Ahmad Malik; literature review: Faisal Ashraf Bhat, Afreen Khanam, Suhail Ahmad Mir, and Amr S. Abouzied; supervision and review and edit: Nafees Ahemad; and conceptualization supervision and review and edit: Sirajuheen Anwar.

Jeba Ajgar Ansari and Jonaid Ahmad Malik contributed equally to this work.