Excipient nanoparticles as cancer therapeutics: Mechanistic actions, delivery and manufacturing perspectives

Abstract

Excipients, conventionally defined as inactive additives, are potential anti-cancer therapeutics at nanoscale against various cancers. This mini-review highlighted nano-excipient potential as anti-cancer therapeutic based on recent literature (2022–2025). Metal/metal oxide nanoparticles stimulate reactive oxygen species production that promotes oxidative damage of cancer cells. Excipient nanoparticles formulating with chitosan/guar gum/arabic gum/pectin/kaolin/peptide additive trigger apoptosis and regulate metastasis. Delivery specificity of excipient nanoparticles can be promoted using targeting ligand (folic acid/hyaluronic acid) or via adaptation of cancer cell membrane that retains the targeting capabilities towards homotypic cancer cells with reduced immune surveillance. Light irradiation/ultrasound/magnetic field could be employed to activate metal-based excipient nanoparticles to initiate hyperthermia, localized electric field, Fenton-like reaction or mechanical forces that directly negate cancer growth with membrane disruption or through intracellular accumulation of cytotoxic excipient nanoparticles acting on malignant tumors. Excipient nanoparticles are expected to have milder therapeutic effects and require a prolonged treatment with higher dosages in comparison to drugs. Being drug-free, they are met with reduced manufacturing challenges such as premature drug leaching, drug instability, uncontrolled drug release, toxic metabolite formation and severe systemic adverse effects due to poor drug targeting.

Introduction

Cancer, as a global burden, is one of the leading causes of death worldwide (Victoir et al., 2024). The International Agency for Research on Cancer (IARC) under World Health Organization (WHO) reported approximately 19.98 million new cases of cancers with over 48 % led to fatality for the year 2022 and the cancer burden is expected to continue rising to 35 million new cases in 2050. Surgery is met with healthy tissue removal (Mukherjee et al., 2024). Radiotherapy induces severe immunosuppression and immune tolerance (Wang et al., 2024a). Poor targeting and multi-drug resistance are the characteristic weaknesses of chemotherapeutic agents (Ning et al., 2024, Victoir et al., 2024). Immunotherapy and cell-based therapy similarly may undergo off-target delivery as well as autoimmune disease or death (Liu et al., 2022). Extracellular vesicles on the other hand could be difficult to mass produce (Grangier et al., 2021).

Excipients are conventionally defined as an additive of a medicine without any therapeutic value (Singh et al., 2023). They can be organic or inorganic, polymeric or oligomeric, as well as natural, semisynthetic or synthetic in nature (Nemoto et al., 2024). Polysaccharides and oligosaccharides, such as pectin, alginate and chitosan, receive a widespread application as excipients, and they have been however advocated as potential anti-cancer agents (Iskandar et al., 2024, Picot-Allain and Neergheen, 2023, Zhang et al., 2023a). With reference to cancer, recent studies suggest that chitosan could be therapeutical as a function of its chemical composition and downstream particulate structure design (Iskandar et al., 2024). Use of chitosan, without the introduction of conventional drugs that exploit the chitosan as matrix carrier instead of therapeutic, could reduce the cumbersome drug formulation processes where drug leaching, drug burst release, drug instability and uncontrolled drug release are concerned. Development of chitosan in a nanoparticulate form enhances its specific surface area to interact with the cancer cells. The chitosan nanoparticles can be further decorated with targeting ligand, permeation enhancer, stimuli-responsive ligand and other functional moieties on their surfaces to target delivery of excipients to the intended cancer sites ranging from cell surfaces, cytoplasmic mitochondria and nucleus. The forms of nanoparticles that can be adapted are solid and liquid nanoparticles. In view of “drug-free” nanoparticulate excipients hold cancer cytotoxic potentials and their anti-cancer efficacy can be modulated through formulation or external stimuli, this review examined the spectrum of anti-cancer activity of various excipients in nanoscale from the perspectives of cancer type and cytotoxicity (Table 1).

“Drug-free” nanoparticles exploit the intrinsic physicochemical properties of excipients to disrupt the tumor microenvironment and cancer cell functions (Singh et al., 2023). Metal oxide, such as cobalt oxide and copper oxide, could stimulate reactive oxygen species generation through catalytic reaction of hydrogen peroxide (H2O2) that produces highly reactive species such as hydroxyl radicals (⋅OH) and superoxide (O2–) which promote DNA oxidative damage of cancer cells and trigger tumor apoptosis (Komitaki et al., 2024, Raj et al., 2024). The nickel oxide nanoparticles, at 100μg mL−1, significantly negated the growth of MDA-MB-231 human breast adenocarcinoma cells to 27.91 % (Aarthi et al., 2025). The cobalt oxide nanoparticles, at 500μg mL−1, reduced the viability of HepG2 hepatocellular carcinoma cells to 35 % (Mahmoudi et al., 2024). At 200μg mL−1 of copper oxide nanoparticles, the A549 adenocarcinoma human alveolar epithelial cell viability was reduced to 52.69 % (Raj et al., 2024). At 100μg mL−1 of composite made of copper oxide nanoparticles and guar gum hydrogel, the viability of HUVEC human umbilical vein endothelial, ACHN renal carcinoma and CaKi-2 human renal cancer cells were reduced to 50 %, 10 % and 10 % respectively, and notably no HEC293 human embryonic kidney cells were survivable (Li et al., 2024a). The additive guar gum could have promoted the contact of copper oxide nanoparticles on the surfaces of target cells and granted them a longer residence duration to exert cytotoxic activity (Zarbab et al., 2023). Nonetheless, leaching of copper oxide nanoparticles to the surrounding normal cells may be prevalent as guar gum lacks cancer cell targeting capacity and is similarly mucoadhesive to the normal cells. Comparatively, it appears that iron oxide nanoparticles do not exhibit strong cancer cytotoxic action despite being formulated with polyglutamic acid (Zhang et al., 2023b), a potential source of anti-cancer glutamic acid (Jain et al., 2022). Clinically, the combination of iron oxide-coated aminosilane nanoparticles with radiotherapy for recurrent glioblastoma cancer treatment was met with several patients experiencing mild heating sensation required for eradication of heat-sensitive cancer cells while 9 deaths were recorded due to tumor progression (Silva et al., 2011).

Metal nanoparticles likewise possess anti-cancer properties that are mediated via reactive oxygen species production (Kaur et al., 2024, Santos et al., 2024). A 100μg mL−1 of silver nanoparticles reduced the viability of HFF-1 fibroblast, U-87 MG malignant glioma and DU-145 human prostate cancer cells to ∼ 70 %, ∼25 % and ∼ 45 % respectively. Hybridizing silver nanoparticles with chitosan-arabic gum hydrogel in the form of nanocomposite (1000μg mL−1) reduced the viability of HT29 human colon cancer and Caco-2 colorectal adenocarcinoma cells to ∼ 20 % with the respective IC50 of the hybrid nanoparticles at 366.1μg mL−1 and 264.5μg mL−1 (Huang et al., 2025). The cancer cytotoxicity of silver nanoparticles is apparently strong with the introduction of chitosan-arabic gum hydrogel. This could be aptly due to chitosan possessing an inherent anti-cancer activity (Iskandar et al., 2024). Arabic gum likewise has been reported to possess anti-genotoxic properties that reduce the aberrant crypt foci formation in rodent with colorectal carcinogenesis induced by azoxymethane (Melo et al., 2024). Further, the chitosan-arabic gum hydrogel may promote cancer cell adhesion and permeability toward the silver nanoparticles. The summative influence enhances the cancer cytotoxic action of the metal nanoparticles. Similar to silver nanoparticles, gold nanoparticles, magnesiumwhitlockite nanoparticles, copper nanoparticles and selenium nanoparticles are cancer cytotoxic (Adam-Dima et al., 2024; Maximiamo et al., 2024; Yao et al., 2024, Zhang et al., 2024a,b). Their cancer cytotoxic activity could be promoted by additives such as chitosan, pectin, kaolin and peptide. Chitosan and pectin could exert both intrinsic and extrinsic apoptosis with PI3K/AKT/mTOR and MAPK/ERK pathway suppression, matrix metalloproteinases downregulation, inhibitory effects on angiogenesis and reduced metastasis tendency, as well as programmed cell death ligand 1 (PD-L1) expression inhibition to promote T cell immunity (Iskandar et al., 2024; Picot-Allain et al., 2023). Kaolin is a reducing agent that stabilizes gold nanoparticles (Yao et al., 2024), while peptide such as matrix metalloproteinase (MMP)-2-cleavable peptide GPLGLAG could selectively activate the metal-complex nanoparticles against the over-expression of MMP-2 in a tumor microenvironment (Zhang et al., 2024b).

The silica nanoparticles have been found to have a marginal cancer cytotoxic effect unless they are derivatized into organosilica of relevant chemistry or introduced onto nanoparticles made of polysaccharide such as alginate (Chen et al., 2024a, Huang et al., 2024, Le et al., 2024, Niu et al., 2021). Polysaccharides, peptides and proteins are widely recognized to be able to control cancer growth (Sagar et al., 2025). A 100μg mL−1 of chitosan nanoparticles reduced the cell viability of NCl-H460 non-small cell lung cancer in vitro to 61.2 % (Abdelaziz et al., 2024). Intra-peritoneal alginate displayed 70 % and 66 % tumor growth inhibition in vivo against solid sarcoma 180 at doses of 100 mg kg−1 and 50 mg kg−1 respectively (Hu et al., 2004). β-glucan nanoparticles have been reported to induce 51.27 % of total apoptosis and 23.90 % necrosis in colon adenocarcinoma cells (Rajabi et al., 2024). Albumin nanoparticles are inclined to reduce cancer viability (Li et al., 2024b). Peptide-incorporated nanoparticles, enhanced by polyethylene glycol and polypeptide guanidinium-functionalized poly(ʟ-lysine) as excipients promoting trans-mucus transport by providing stealth effect that evades immune clearance and facilitates cellular uptake via strong electrostatic interaction, pose as a relatively strong cancer therapeutic (Hussain et al., 2019, Yang et al., 2022).

Targeting ligand is one of the most critical excipients in the development of cancer nanomedicine. It entails cancer target-specific delivery of therapeutics thereby minimizing the systemic adverse effects and bystander effects (Sagar et al., 2025). The adoption of active targeting ligands, such as folic acid or hyaluronic acid to decorate the excipient nanoparticle surfaces, is expected to enhance the therapeutic efficacy through strong binding of excipient nanoparticles to cancers with overexpressed folate receptor or CD44 receptor instead of normal cells (Kunjiappan et al., 2024, Zhou et al., 2024). The late innovation adopts cancer cell membrane that retains the inherent active targeting capabilities to recognize the antigenic diversity on the homotypic cancer cell surface and homologous tumors while protecting the entire delivery system from immune surveillance (Guo et al., 2024, He et al., 2024).

Read also our overview article on World Cancer Day here:

excipients formulation