Three stages comprise the development of nanomedicine: the first took place between 1964, when the structure of liposomes was discovered, and 1995, when the US Food and Drug Administration (FDA) approved liposomal doxorubicin (DOX), also marketed as Doxil^® (Viana et al., 2021). The clinical validation and commercialization of nanomedicine constituted the second phase, which ran from 1995 to 2007 (Chen et al., 2022c). The third stage, from 2007 to the present, represented a period of rapid advancement in nanomedicine, marked by continuous emergence of various innovative technologies. Nanoparticles (NPs) are microscopic particles with sizes ranging from 1 to 100 nm. Due to their unique physical properties such as conductivity, stability, and optical characteristics, nanoparticles have become ideal subjects for research in biology and materials science (Shi et al., 2017; Aghebati-Maleki et al., 2020). Nanoparticles have been proven to have promising applications in various fields including medicine, pharmacy, tissue engineering, environment, energy, electronics, biomolecular and protein diagnostics, and cellular engineering (Hou and Liu, 2023). They are categorized based on their properties, shapes, and sizes into different classes, including carbon-based NPs, metal NPs, ceramic NPs, polymer NPs, lipid-based NPs, and virus-based NPs (Sarma et al., 2021; Sun et al., 2023). Polymer NPs, lipid NPs, and virus NPs belong to organic NPs (Bodunde et al., 2021; Vargas-Nadal et al., 2022), while carbon-based NPs, metal NPs, ceramic NPs, and semiconductor NPs belong to inorganic NPs (Bodunde et al., 2021; Li et al., 2019; Zhou et al., 2017; Greene et al., 2021), as detailed in Table 1.

Traditional drugs have long been limited in clinical applications due to issues such as water solubility, stability, pharmacokinetics, low bioavailability, poor targeting, and toxicity (LI et al., 2023a). The emergence of nanomedicine has overcome these limitations and made significant strides (Altemimi et al., 2024; Zambonino et al., 2023). The application of nanomaterials in clinical diseases offers distinct advantages (Figure 1). Firstly, compared to most traditional drugs, nanomaterial formulations typically contain multiple functional components, each capable of exerting different effects on drug efficacy and safety throughout the treatment process (Zhou et al., 2021; Briolay et al., 2021; Mitchell et al., 2021). Secondly, some nanomaterials such as gold nanoparticles (AuNPs) possess unique electromagnetic properties, making them useful for photothermal therapy, photodynamic therapy, radiation therapy, X-ray imaging, computed tomography (CT), etc. (Fan et al., 2020; Batool et al., 2023). Thirdly, nanomaterials can distinguish pathological tissues from normal tissues, primarily based on the interactions between nanoparticles and biological tissues in vivo (Fan et al., 2020; Batool et al., 2023). Nanomedicine is an evolving field involving materials, devices, and technologies at the nanoscale, which can be used for the diagnosis, treatment, and prevention of clinical tumors (Elmowafy et al., 2023; Zheng et al., 2024). Current applications of nanoparticles include drug delivery and treatment such as nanoparticle Drug Delivery Systems (NDDS) (Ordikhani et al., 2021; Tu et al., 2023), diagnostics and imaging (Wang, 2020), tissue engineering and regenerative medicine (Wang et al., 2022), and immunotherapy (Li et al., 2023b). Additionally, the clinical application of nanomedicine is moving towards personalized medicine and integrated diagnosis and treatment to achieve more efficient clinical care, bringing about more innovations and breakthroughs in the field of medicine (Cui et al., 2024).

Personalized therapy, also known as individualized medicine or precision medicine, aims to reveal differences in individual responses, disease mechanisms, and risk factors during the disease process through high-throughput biomedical testing methods such as DNA sequencing, proteomics, imaging, and monitoring devices. This approach then determines how to optimize treatment, monitoring, or prevention of diseases to achieve the best clinical outcomes (Zhan et al., 2022; Desar and Rothermundt, 2023; Corrado and Garganese, 2022). It is widely recognized that there are certainly heterogeneities in the development of many diseases, so when diagnosing, treating, or monitoring specific patients, therapy must be tailored or personalized based on the unique biochemical, physiological, environmental exposures, and behavioral characteristics of individuals (Fujiwara et al., 2022).

Tumor or cancer is a dynamic disease, characterized by the transformation of non-malignant cells into malignant ones primarily through a series of pathological changes. This transformation leads to enhanced cell proliferation, evasion of growth suppression and cell death signals, induction of angiogenesis, and ultimately activation of programs that cause tissue invasion and metastasis (Brown, 2023; Mo et al., 2021). The occurrence and progression of tumors do not follow a fixed process but should be viewed as overall instability in key cellular processes. Even after completing malignant transformation, tumors continue to develop dynamically, undergoing continuous evolution. Eventually, they give rise to tumor masses composed of cancer cells with different molecular characteristics, exhibiting varying levels of sensitivity to cancer treatment (Zhang and Fu, 2021).

This heterogeneity may result in the uneven distribution of genetically distinct tumor cell subpopulations between and within disease sites (spatial heterogeneity), or temporal changes in the molecular composition of cancer cells (temporal heterogeneity) (Li et al., 2022). Therefore, accurately evaluating tumor heterogeneity and implementing personalized treatments targeting this heterogeneity are crucial in the clinical diagnosis and treatment of cancer. The development of molecular diagnostic techniques allows for a more accurate understanding of the genetic characteristics and molecular biomarkers of tumors, providing crucial information for devising personalized treatment plans (Guan et al., 2023). By analyzing the genome, transcriptome, and epigenetics information of a patients, clinicians can more accurately determine treatment strategies (Wu et al., 2019; Han et al., 2022). At the same time, immunotherapy and targeted therapy are important directions in the field of personalized cancer treatment. Immunotherapy harnesses the patient’s own immune system to attack cancer cells, while targeted therapy intervenes in the cancer process by targeting specific molecular targets (Letai et al., 2022). Personalized tumor treatment is a promising field that offers new possibilities for improving the treatment outcomes and survival rates of cancer patients. With advancements in technology and medicine, we can expect to see more personalized treatment options emerging, bringing hope to cancer patients. Currently, nanomedicine, as an emerging approach to tumor diagnosis and treatment, is mainly applied in personalized tumor treatment for targeted drug delivery, imaging diagnosis, and treatment monitoring (Shrestha et al., 2023; Alghamdi et al., 2022; Yang et al., 2020).

As an advanced approach to tumor diagnosis and treatment, nanomedicine combines nanomaterials with medical science, offering innovative methods for personalized cancer therapy. Currently, the application of nanomedicine in personalized cancer treatment is mainly focused on targeted drug delivery, imaging diagnosis, and treatment monitoring. In the area of targeted drug delivery, nanomaterials can be designed with specific biocompatibility and targeting capabilities, allowing for precise delivery to tumor tissues or cancer cells, thereby minimizing side effects on normal tissues (Shrestha et al., 2023; Alghamdi et al., 2022). For imaging diagnosis, nanomedicine provides efficient tools for early diagnosis and real-time tumor monitoring. Nanoprobes and nano-contrast agents, with their unique optical, magnetic, and radioactive properties, can significantly enhance imaging quality, making cancer cells more visible in early diagnostic stages (Yang et al., 2020). This precise imaging technology not only increases the likelihood of early cancer detection but also enables doctors to assess tumor size, location, and spread with greater accuracy, providing essential support for subsequent treatment decisions (Pallares et al., 2022). In treatment monitoring, nanotechnology also plays a crucial role. By designing smart nanomaterials, it is possible to monitor and provide real-time feedback on treatment effectiveness through drug release tracking or biomarkers produced during tumor response, which can help physicians adjust treatment plans in a timely manner, improving treatment efficacy and the level of personalization (Ju and Cho, 2023). Overall, the application of nanomedicine in personalized cancer treatment greatly expands the limitations of traditional therapies, making treatment more precise, effective, and personalized. With the continuous advancement of nanotechnology, the potential of nanomedicine in the field of oncology will further unfold, providing cancer patients with more optimized treatment options and extended survival. In the future, as the design and fabrication of nanomaterials improve, nanomedicine is expected to play a more critical role in precision oncology, becoming an indispensable part of cancer diagnosis and treatment.

Measurable biomolecules that can be found in blood, other tissues, or bodily fluids like saliva and urine are known as tumor biomarkers. By determining their expression levels, it is possible to assess the presence of tumors in the body and their malignancy (Jardim et al., 2021). Biomarkers may include proteins, carbohydrates, or nucleic acids such as DNA, RNA, circRNA, mainly secreted by the organism or tumor cells (Deng et al., 2022). Assessing particular biomarker levels can assist track the effectiveness of treatment and help detect cancers or tumor recurrence early. However, biomarker detection is subject to certain limitations, including low biomarker concentrations in body fluids, variability in biomarker abundance within patients, and heterogeneity across different times and tissues (Pessoa et al., 2020). Nanotechnology offers the ability for high selectivity, sensitivity, and simultaneous measurement of multiple targets. Nanomaterials and nanoparticles can be used to improve biosensors and provide targeted imaging. Meanwhile, Because of the higher surface area-to-volume ratio that nanoparticles offer, biosensors are better able to detect the presence of particular biomolecules (Boehnke et al., 2022). Semiconductor NPs, metal NPs, and polymer NPs are three commonly used types of NPs probes for detecting tumor biomarkers (Combes et al., 2021; Amri et al., 2021) (Figure 2A).

Semiconductor NPs are commonly used for the detection of biomarkers due to their unique properties, including high quantum yield and molar extinction coefficient, broad absorption spectrum and narrow, efficient Stokes shift, high resistance to photobleaching, and excellent degradation resistance (Fatima et al., 2021). Li et al. (2011) proposed a novel approach for dual-protein immunoassay based on dual-color quantum dots. In this method, two lung cancer biomarkers, carcinoma-embryonic antigen (CEA) and neuron-specific enolase (NSE), were targeted (Li et al., 2011). CEA, one of the most common cancer biomarkers, has been utilized for monitoring cancer treatment efficacy and predicting tumor recurrence in late-stage cancer patients’ post-surgical resection (Hori et al., 2022). NSE is an enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate, and it is associated with neuroendocrine cells, small cell lung carcinoma, and pancreatic islet cell tumors (Sandroni et al., 2022). After secretion, they can be detected at concentrations exceeding 15 ng/mL, with detection limits for each reaching 1.0 ng/mL. The study results indicate that CEA and NSE can be sensitively detected using a conventional 96-well fluorescence plate reader, with detection limits of 1.0 ng/mL for each target. Within the calibrated range, this approach demonstrates excellent precision for each target, with an accuracy of around 0.53%. Furthermore, the method has been successfully applied to the determination of dual biomarkers in actual samples, showing no cross-reactivity. It also exhibited good correlation when compared with traditional assays for CEA and NSE in human serum samples from 25 individuals (Hu et al., 2023). Additionally, research has shown the development of a precise enzyme-induced targeting gold nanoparticle system mediated by iRGD/AuNPs-A&C, which utilizes tumor-targeting penetrating peptide iRGD modified gold NPs. This system exhibits high permeability and aggregation in breast tumor cells (Liang et al., 2023). Tong et al. (2010) prepared Cy5-conjugated poly (lactic acid) (Cy5-PLA) nanoparticles through nanoprecipitation. They conjugated Cy5-PLA NPs with oligonucleotides (aptamers) binding to prostate-specific membrane antigen (PSMA). Aptamers possess high affinity and strong binding specificity to their respective targets, including ions, bacteria, peptides, viruses, lipids, and even whole cells. Polymer NPs (Cy5) bound by A10 RNA aptamer can bind to PSMA. Cy5-PLA/aptamer NPs can only bind to cells that respond positively to PSMA, such as LNCaP and canine prostate cancer cells; they are unable to bind to PC3 cells, which respond negatively to PSMA (Tong et al., 2010).

Prior to invading the circulatory microvasculature and lymphatic system, the primary tumor initially invades the surrounding tissues. Subsequently, they survive in the bloodstream and migrate to distant tissues’ microvasculature, ultimately extravasating and surviving in the microenvironment of distant tissues. This provides an appropriate heterogeneous microenvironment for the development of macroscopic secondary tumors (Xiao and Yu, 2021). Accurately identifying circulating tumor cells (CTCs), or metastatic cancer cells in the bloodstream, may influence the prognosis and diagnosis of cancer (Lin et al., 2021). CTCs have been extensively researched as a component of liquid biopsy because of their potential uses. Compared to tumor biomarker detection, CTCs detection has the advantage of directly and specifically identifying and isolating tumor cells in the bloodstream, providing direct information on metastasis risk and cancer progression. It is widely used for early detection and dynamic monitoring of metastatic cancers, offering significant advantages in metastasis risk assessment, prognosis analysis, and personalized treatment evaluation. However, its clinical application is limited by the complexity and high cost of the detection process, as well as the need for specialized equipment and technical expertise.

Nanomaterials offer significant advantages for CTCs detection as they can efficiently adsorb targeting ligands with the ability to recognize specific molecules on cancer cells (Chen et al., 2019; Jarockyte et al., 2020; Choi et al., 2010). Thus, the isolation of CTCs has good specificity and recovery rates, improving the sensitivity of detection. Research has reported various types of nanomaterials, such as metal NPs, semiconductor NPs, carbon nanotube NPs, and polymer NPs for CTCs detection, showing potential to advance cancer diagnosis and prognosis (Jarockyte et al., 2020; Wu et al., 2022) (Figure 2B). Zhao et al. (2024) constructed a surface with nanoscale roughness by coating a cellulose acetate membrane with nanoparticles formed by the polymerization of melamine and furfural, enabling the efficient capture of sparse CTCs in blood samples. Subsequently, the CTCs on the surface can be quantitatively detected by colorimetry with the aid of a COF-based nanozyme, achieving a detection limit (LOD) as low as 3 cells/mL (Zhao et al., 2024). Meanwhile, Lu et al. (2023) constructed a chip substrate by crosslinking silica nanoparticles layer-by-layer on glass slides using polyacrylic acid. Polyacrylic acid was immobilized as a spacer, with capture ligands attached to it. The results demonstrated that this chip could be integrally applied for CTC capture, post-treatment, and imaging detection. In samples with 9 cells/mL and clinical blood samples (7.5 mL), the detected cell counts were 33 and 40, respectively, with a detection rate of 100% for positive samples (Lu et al., 2023). Overall, nanomaterials efficiently capture and enrich rare CTCs through their surface properties; they improve detection sensitivity by combining with specific molecules to recognize tumor biomarkers; and they can enhance imaging signals, thereby increasing detection accuracy. Nanomaterials significantly enhance the sensitivity, specificity, and operability of tumor cell detection, advancing the development of early tumor diagnosis and personalized treatment.

Apart from the ex vivo diagnosis of cancer through the identification of cancer cells and biomarkers in liquid biopsy samples, there are many advantages to identifying cancer tissue in vivo for cancer diagnosis and treatment. The continuous advancement of technology has improved diagnostic imaging techniques, enabling the detection and diagnosis of early-stage diseases (Le Fur et al., 2021). Although various imaging modalities such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) are widely used in clinical practice, each imaging technique has its advantages and limitations. Currently, the development of integrated PET/MRI scanners has opened new prospects for cancer diagnosis, treatment, and follow-up. In recent years, radionuclide imaging, fluorescence imaging, magnetic resonance imaging, ultrasound imaging, photoacoustic imaging, and multimodal imaging are all examples of nanoparticle-based tumor molecular imaging methods (Pellico et al., 2017) (Figure 2C).

Molecular imaging uses multimodal imaging to obtain information at the biological and cellular levels, thereby tracking biological pathways and discovering many typical tumor characteristics. In this context, contrast agents (CAs) based on nanoparticles (NPs) can improve the biocompatibility and biodistribution of probes, extend the blood half-life to achieve accumulation at specific targets, and ensure non-toxicity to surrounding tissues (Milan et al., 2022; Fernández-Barahona et al., 2018; Ko et al., 2022; Yin et al., 2024). Additionally, CAs can deliver drugs or conventional therapeutic agents simultaneously, achieving dual diagnostic and therapeutic effects, thereby advancing the process of personalized treatment. NPs have been widely studied in preclinical stages as imaging probes for dual MRI/PET tumor imaging, with the most common carriers being iron oxide NPs and silica NPs (Karageorgou et al., 2023; Zhao et al., 2023).

The capacity of magnetic iron oxide nanoparticles (NPs), which are usually made of magnetite Fe₃O₄ and maghemite γ-Fe₂O₃, to shorten T2 and T2* relaxation durations makes them useful for MRI imaging, especially in the liver, spleen, and bone marrow. They can be divided into four categories based on size: monocrystalline iron oxide (MION), ultrasmall superparamagnetic iron oxide (USPIO), superparamagnetic iron oxide (SPIO), and micrometer-sized paramagnetic iron oxide (MPIO) (Qiao et al., 2023). Xie et al. (2010) tagged human serum albumin matrices with Cy5.5 dye and ⁶⁴Cu-DOTA after encasing dopamine-modified Fe3O4 NPs. Injection of these nanoparticles into U87MG xenograft mouse models revealed higher signal-to-noise ratios in PET and NIRF imaging compared to MRI, indicating higher sensitivity. Conversely, MRI scans after nanoparticle injection exhibited clear but uneven distribution due to their high spatial resolution (Xie et al., 2010). Lee et al. (2008) conjugated RGD with ⁶⁴Cu-labeled Fe₃O₄ nanoparticles and conducted imaging on U87MG mouse models, where both PET and MRI confirmed nanoparticle accumulation mediated by αvβ3 integrin binding. Kim et al. (2013) injected ⁶⁸Ga-labeled Fe₃O₄ NPs into colorectal cancer nude mice and found suppression of cancer cell proliferation, induction of apoptosis, and cancer cell death. PET/MRI scans yielded detailed pictures and accurate tumor area measurement (Kim et al., 2013). In addition, iron nanoparticles can serve as an adjunct in clinical imaging diagnosis to help differentiate between benign and malignant tumors. A prospective study in pediatric cancer patients found that the iron supplement Ferumoxytol can enhance image contrast in MRI scans, aiding in the clearer visualization of tissue and lesion details, and assisting in distinguishing between benign and malignant lymph nodes in children with cancer (Muehe et al., 2020).

Silicon dioxide-based NPs are considered ideal biocompatible matrices that can be integrated into imaging probes, with two main categories: solid (SiNPs) and mesoporous (MSNs). MSNs are usually used for molecular, multimodal, CT, MRI, and PET imaging, whereas SiNPs are commonly used as optical imaging agents. MSNs are created using sol-gel techniques with surfactant templates, possessing high surface areas, tunable sizes, shapes, and pore structures, as well as appealing features easily functionalized through synthetic approaches (Shuai et al., 2023). Imaging of sentinel lymph nodes (SLNs), as the first line of defense against primary tumor metastasis, is regarded as a crucial strategy clinically for tracking tumor metastasis. Using various conjugation strategies, Huang et al. integrated three imaging probes—the positron emission radiotracer ⁶⁴Cu, the T1 contrast agent Gd-DTTA, and the near-infrared (NIR) dye ZW800—with PET and MRI imaging probes dispersed on the surface and inside the mesoporous channels of NPs. Compared to normal SLNs, multifunctional MSNs probes exhibited faster uptake rates and higher uptake ratios in T-SLNs, confirming the feasibility of these MSNs probes as contrast agents for mapping SLNs and identifying tumor metastasis (Huang et al., 2012) (Figure 2C).

Additionally, ultrasound has long been used in clinical practice for cancer detection and image-guided tissue biopsy. For decades, stable perfluorocarbon microbubbles have been used as contrast agents in ultrasound imaging. However, the large size, poor stability, and short cavitation activity of microbubbles have limited their application in cancer imaging and therapy (Sabuncu and Yildirim, 2021). Nanoparticles is expected to address this issue. Research by Pucci et al. found that piezoelectric hybrid lipid-polymer nanoparticles can effectively encapsulate non-genotoxic drugs (nutlin-3a) and be functionalized with peptides (ApoE) to enhance their passage through the blood-brain barrier. Under ultrasound stimulation, the nanocarrier can reduce cell migration, actin polymerization, and glioma cell invasiveness while promoting apoptotic and necrotic events (Pucci et al., 2022). Zhang et al. (2023) developed a novel nanoparticle with a PLGA outer layer, loaded with perfluoropentane (PFP), paclitaxel (PTX), and an anti-miR-221 inhibitor, naming it PANP. RAW-PANPs successfully stopped the growth and progression of tumors in vivo as well as the proliferation of TNBC cells in vitro. These therapies did not harm the kidneys, liver, or heart. In addition to creating a chemotherapeutic system that targets cancer cells and is delivered by macrophages and activated by ultrasound, their research also showed promise for clinical use by demonstrating a miRNA-based method to increase drug sensitivity in cancer cells (Zhang et al., 2023).

PTDDS is primarily based on the enhanced permeability and retention (EPR) effect in tumor tissues, delivering drugs to tumor tissues rather than normal tissues. Drug-loaded NPs, such as liposomes and polymer NPs, are naturally engulfed through physiological processes like cellular uptake to achieve targeted drug distribution (Maeda et al., 2000). Organic NPs, including liposomes and polymer NPs, are widely used in PTDDS (Batool et al., 2023; Tian et al., 2022b) (Figure 3A).

Compared to the low selectivity and affinity of PTDDS, ATDDS utilize various targeting molecules such as proteins, antibodies, small molecules, or nucleic acids to modify drug-loaded NPs. These modifications enable the directed delivery of drugs to tumor tissues through targeted interactions (Tian et al., 2022b). The main types of ATDDS include receptor-mediated NPs, peptide-mediated NPs, and small molecule-mediated NPs (Batool et al., 2023; Mi, 2020) (Figure 3A).

ERTDDS refers to the targeted distribution of drug-loaded NPs in the body through physical and chemical effects such as magnetic, thermal, acoustic, optical, electrical, and pH effects (Mi, 2020; Hu et al., 2022; Zhou et al., 2024b) (Figure 3B). Traditional drug delivery systems are not ideal as they fail to maintain stability at the target site and promote drug release. Over time, ERTDDS design has emerged as a research hotspot. ERTDDS can specifically react to endogenous or exogenous stimuli, such as physical properties (like photosensitivity), chemical properties (like pH sensitivity and reduction sensitivity), and biological properties (like matrix metalloproteinases), in order to comprehend the physiological differences between tumors and normal tissues (He et al., 2020; Cong et al., 2022). Only in proximity to the site of drug action can ERTDDS react to internal and external environmental stimuli, releasing medicines in tumor tissue while preserving stability in other tissues. As a result, it lessens toxicity and adverse effects while enhancing the anti-tumor activity.

Photodynamic therapy (PDT) and photothermal therapy (PTT) are the foundations of light-sensitive TDDS, a tumor treatment technique. After NPs reach the tumor site under light conditions, photosensitizers or photothermal agents absorb light and release reactive oxygen species, singlet oxygen, or induce local high temperatures (Guo et al., 2023). This selectively and efficiently generates cytotoxic activity, killing tumor cells while protecting normal tissues. Xu et al. (2018a) prepared silk fibroin NPs (SFNPs) loaded with the dye indocyanine green (ICG) to construct a therapeutic nanoplatform (ICG-SFNPs) for photothermal therapy of glioblastoma. In vitro studies demonstrated the slow release of ICG from ICG-SFNPs, with only (24.51 ± 2.27)% of encapsulated ICG released even after 72 h. Moreover, compared to free ICG, ICG-SFNPs exhibited a more stable photothermal effect upon exposure to near-infrared radiation. Local near-infrared irradiation rapidly increased the temperature at the tumor site, leading to tumor cell death. After treatment, tumor growth was completely suppressed, with a relative tumor volume of (0.55 ± 0.33), whereas free ICG exhibited a volume of (33.72 ± 1.90) (Xu et al., 2018a). Human blood and interstitial fluid normally have an alkaline pH of 7.4, whereas the tumor microenvironment has an acidic pH of about 5.6. This slight acidic environment is primarily due to the rapid proliferation of tumor cells and excessive accumulation of lactate (Johung and Monje, 2017). Therefore, numerous studies have utilized the pH difference between tumor tissue and normal tissue to construct drug delivery systems based on pH-responsive materials. During the transition from a weakly alkaline to a slightly acidic environment, many delivery methods may modify their physicochemical features, such as swelling and enhanced solubility. These further activate the release of packed drug molecules, which serve a targeted role in tumor therapy (Xu et al., 2018b). Li et al. (2012) synthesized a pH-sensitive dual-targeted drug carrier (G4-DOX-PEG-Tf-TAM) composed of PAMAM dendrimers conjugated with transferrin (Tf) and tamoxifen (TAM), aiming to enhance blood-brain barrier transport and increase drug accumulation in glioma cells. Their research showed that at pH 4.5, the release rate of DOX was 32%, while at pH 7.4, it was 6%, indicating relatively rapid drug release under weakly acidic conditions and stability in normal physiological environments (Li et al., 2012). Due to various reasons, including overexpression of drug efflux pumps like P-gp and inherent resistance caused by cancer stem cells (CSCs), breast cancer cells can develop resistance to treatment. Disulfiram (DSF) serves as an inhibitor of P-gp and CSCs. Swetha et al. developed tumor extracellular pH-responsive nanoparticles using PLGA conjugated with coenzyme Q10 polyol (TPGS) surface-modified with histidine ([DD]NpH-T). In vitro studies demonstrated that [DD]NpH-T exhibited increased drug release at pH 6.8, enabling better penetration of 3D tumor spheroids, reducing serum protein adsorption, and enhancing cytotoxicity against docetaxel-resistant breast cancer cells. In vivo studies showed significantly increased plasma area under the curve and tumor drug delivery with [DD]NpH-T, thereby improving the in situ anti-tumor effect in breast cancer, enhancing ROS expression levels and cell apoptosis, while reducing P-gp expression and preventing lung metastasis (Swetha et al., 2023).