Emerging nanotherapeutics for HPV-associated cancers: current advances, challenges, and future directions

Abstract

Human Papillomavirus or HPV are viruses belonging to the family Papillomaviridae, these have double-stranded circular DNA. HPV is among the most common sexually transmitted infections which affect over 50% of the adult population. It is also responsible for approximately 5% of total cancer cases. The cancers associated with HPV include cervical cancer, vulvar cancer, vaginal cancer in females, and penile cancer in males. Apart from genital cancer, it also causes other cancers, such as anal cancer, oral cancer and oropharyngeal cancer. Traditional therapeutic methods like surgery, chemotherapy, radiotherapy, and others come with many drawbacks, such as non-specificity towards tumorous cells and other harmful effects on other non-tumorous cells. Advancement in nanotherapeutics has enabled us to precisely target cancer cell for better therapeutic outcome. These nanoparticles help in precise drug delivery, and they can also be combined with other treatments like gene therapy or immunotherapy for better results. This review synthesizes findings from PubMed and Scopus databases using keywords such as “nanoparticles” “HPV” and “cancer” to provides a comprehensive overview of HPV-related cancer, their current treatment approaches and their limitations, and advanced nanotherapeutic approaches for HPV-related cancers such as targeted drug delivery using nanoparticles, nanoparticle-mediated radiotherapy, immunotherapy, and gene therapy. Our review findings suggest that advanced nanotherapeutics have the potential to significantly enhance therapeutic outcomes in HPV-related cancers.

Introduction

Human papillomaviruses (HPVs) are ds DNA viruses. HPV primarily spreads through direct contact between the skin or mucous membranes and it enters the body through cuts or abrasions. HPV infection is the most prevalent sexually transmitted infection affecting every second sexually active adults of both genders. HPV can lead to various conditions, such as common warts, genital warts, and genital cancer [1]. Broadly, HPVs comprise two groups: low-risk and high-risk. Low-risk HPV infection mainly leads to lesions or warts around the genitals, anus, and throat, and high-risk HPV infection could lead to cancer of several types. Cervical cancer is the major cancer caused by HPV; it is among the most common malignancies in women. HPV 16 and 18 are responsible for 70% of cervical cancer cases [2, 3]. Other HPV-related cancers in women are vaginal cancer and vulvar cancer [4, 5]. HPV also affects male genital parts by causing penile cancer [6]. Other cancers caused by HPV are anal cancer and oropharyngeal cancer [7]. Taking altogether HPV causes approximately 5% of cancers, claiming lives of more than 400,000 individuals per year [8]. Traditional therapeutic methods like chemotherapy, radiotherapy, and others come with many drawbacks, such as non-specificity towards tumorous cells and other harmful effects on other non-tumorous cells. With the advancement of therapeutics, it is now possible to target cancer cells with the help of nanoparticles. Various nanocarriers, such as micelles, liposomal nanoparticles, dendrimers, metallic and non-metallic nanocarriers, and virus-like particles, could serve therapeutic purposes for us [9, 10]. Current article is aimed to review current status of nanotherapeutics approaches for HPV related cancer, their challenges and future prospectives. In this review article, we have discussed HPV and related cancer, current treatment options, and associated limitations. Further, we have discussed advanced nanotherapeutic approaches applied in HPV-related cancer therapeutics, including targeted drug delivery using nanomaterials, nanoparticle-augmented radiotherapy and immunotherapy, the use of nanomaterials in therapeutic vaccines against HPV, and the very recent advancement of nano mediated gene therapy, including nano-Clustered Regularly Interspaced Short Palindromic Repeats (nano-CRISPR). Additionally, we have focused not just on the clinical applications, but also on the challenges faced in translating these advanced therapies into real-world treatments and the future outlook for their success.

HPV and cancer

HPVs are viruses of the Papillomaviridae family, having a double-stranded and circular DNA genome of approximately 8 thousand base pairs [11]. HPV infection is the most common sexually transmitted infection (STI) in the world; nearly all sexually active men and women will contract an HPV infection at some point [12]. HPVs initially target undifferentiated basal epithelial cells; subsequently, viral offspring are generated within differentiated daughter cells located in the upper layers of the epithelium, and from there, they spread to the deeper layers of the epithelium [11]. HPV have more than 150 subtypes which could be categorized as high-risk HPV e.g. subtypes 16 and 18 and low-risk HPV groups e.g. subtypes 11 and 6 [13]. Low-risk HPV infections typically cause mild precancerous lesions and genital warts, while high-risk HPV infections are linked to the development of cancer [14].

HPV infection is linked to a number of cancers, including oropharyngeal, penile, vulvar, cervical, vaginal, and anal cancers [15] (Fig. 1). HPV oncoproteins E5, E6 and E7 are key drivers of cancer, HPV oncoproteins E5, E6, and E7 drive cancer progression by promoting uncontrolled proliferation and inhibiting apoptosis. E7 degrades pRb to induce S-phase re-entry, E6 targets p53 for degradation, and E5 enhances EGFR signaling, creating a pro-tumorigenic environment [16]. Among females, cervical cancer is a major malignancy caused by HPV infection. It is a malignancy of the cells of the cervix. According to GLOBOCAN 2020 data, it is the 4th most prevalent cancer in females and the 9th most common cancer overall [17]. Almost every case of cervical cancer is related to a sustained chronic infection with high-risk HPV [18]. Regular screening using an HPV test or Pap smear can effectively prevent the majority of cervical cancers by enabling healthcare providers to detect and remove abnormal cells before they progress to cervical cancer [19]. Other female cancers caused by HPV are vaginal and vulvar cancers. Vaginal cancer can be described as a localized cancer that doesn’t show signs of cervical or vulvar cancer, nor does it have a recent history of either within the last 5 years. It is a rare type of cancer, comprising 1–2% of all female reproductive tract cancers [20]. Vulvar cancer is a squamous cell carcinoma affecting the external genitalia of the female reproductive system, the vulva. It is also a relatively rare kind of cancer, mostly associated with HPV infection [21]. Men’s HPV infections cause penile cancer. Typically, this cancer develops on or beneath the foreskin, with HPV-16 or HPV-18 being associated with about 31% of cases. [22]. Other HPV-associated cancers include oropharyngeal cancer and anal cancer. Oropharyngeal squamous cell carcinoma (OPSCC), also called tonsil cancer or throat cancer, is the term used for cancer affecting the central section of the pharynx, specifically the oropharynx. Oropharyngeal cancer could either be HPV-positive or HPV-negative. Nearly 90% of HPV-positive oropharyngeal cancers are caused due to HPV 16 [23]. Anal cancer is a type of cancer that originates in the anus. About 90% of anal cancer cases are linked to HPV (particularly high-risk types like HPV 16 and 18) [24].

Fig. 1.

Different types of cancers caused by HPV with respective occurrence percentages and the major HPV subtypes associated with different cancers

Overall, HPV infections are related to almost 5% of total human malignancies [24], making them one of the most prevalent cancer causes. And therapeutic advancements, including nanotherapeutics against these, hold paramount importance in the better management of cancer and overall public health.

Current treatment options for HPV related cancers

Chemotherapy, radiotherapy and surgery are most commonly used treatment method for cancer. These could be used either alone or in combination with other [25, 26]. Among these, surgery is often used as primary method for localized cancer. The selection of a surgical procedure depends greatly on the stage of the disease and how far it has spread. Presently, surgical options for treating cervical cancer encompass procedures such as hysterectomy (total or radical), trachelectomy, “loop electrosurgical excision procedure” (LEEP), and conization. Hysterectomy refers to the surgical removal of the uterus and the cervix; A radical hysterectomy involves the surgical removal of the uterus, cervix, both ovaries, both fallopian tubes, and surrounding tissue. A total hysterectomy involves the surgical removal of the entire uterus, including the cervix [27]. LEEP is a minimal invasive surgical procedure in which a thin wire loop with electrical current is used to cut abnormal cervical tissue. Conization or cone biopsy refers to surgical removal of a cone-shaped cervical cancer tissue [27]. The term “trachelectomy” describes the surgical excision of the cervix while leaving the uterus intact. In order to preserve fertility, it is frequently done on young women with early-stage cervical cancer [28]. These surgical approaches could be used in combination therapy with radiotherapy or chemotherapy in cervical cancer [29]. For vaginal cancer, surgical approaches include local excision, radical hysterectomy, partial vaginectomy, and pelvic exenteration, usually coupled with the assessment of the lymph node [30]. For vulvar cancer, surgical methods such as vulvectomy with or without adjuvant or neoadjuvant therapy (chemotherapy or radiotherapy) are considered the gold standard because of complete removal of tumor, and generally include wide and radical local excision of the tumor or radical vulvectomy [31]. For penile cancer, topical therapy, surgery, or radiotherapy are used depending on the extent of the disease [32]. Penile cancer surgery includes circumcision (removal of the foreskin), glans resurfacing (surgical alteration of the glans penis surface), hemi-glansectomy (partial removal of the glans penis), glans amputation (complete removal of the glans penis), or total glansectomy (complete removal of the glans penis and surrounding tissues) [32, 33]. For oropharyngeal cancer, neck dissection and primary tumor resection are mostly done in HPV-positive patients [34]. For anal cancer, the most preferable treatment options are radiotherapy and chemotherapy, and surgical approaches are only limited to the management of lower-risk tumors [35]. As HPV-related cancers widely affect the genital parts of both males and females, fertility retention is a key challenge associated with invasive treatment approaches such as surgery, and thus it is recommended to perform fertility sparing surgery or organ sparing surgery [32, 36]. Therefore, there is a need for more precise, less invasive, and targeted therapies, such as nanotherapeutics, which hold promise in overcoming these limitations.

Radiotherapy and chemotherapy are also used for the treatment of HPV-related cancers. These are used either independently or as adjuvant/neoadjuvant therapy with surgery. Adjuvant therapy is administered after the primary treatment to lower the risk of cancer recurrence, while neoadjuvant therapy is administered before the primary treatment to shrink the tumour [37]. Radiotherapy refers to use of high energy beam such as X-rays to kill cancerous cells and is particularly effective for rapidly growing cancers [38]. Chemotherapy refers to the use of drugs such as cisplatin to treat cancer, these drugs could be given via oral route or intravenously [39, 40]. But the drawbacks associated with these are their toxicity and non-specificity; they often target cancerous as well as normal tissues, leaving a harmful effect [41]. To overcome these drawbacks of conventionally practiced therapies, more targeted therapies are developing, and various nanotherapeutic-based approaches are now being extensively explored for cancer treatment [42].

Advanced nanotherapeutics for HPV-related cancers

Nanotherapeutics is the use of nanotechnology in the field of medicine and therapy, while nanotechnology itself is the creation and application of materials and devices with functional components at the nanometer scale [43]. Nanotherapeutics has several advantages over traditional chemotherapy, including increased stability and biocompatibility, enhanced permeability and retention effects, and more accurate targeting [44]. Nanotherapeutic approaches are also being explored for more precise and effective treatment of cancers, including HPV-related cancers. In cancer treatment, nanotechnology could be used for precise drug delivery and could also be augmented with radiotherapy, immunotherapy, and gene therapy to yield better therapeutic outcomes [45–48]. Further nano-phytochemicals or nano-herbal formulations enhance the therapeutic potential of phytomolecules like lycopene, curcumin and quercetin for HPV-associated cervical cancer by improving bioavailability, targeted delivery, and reducing systemic toxicity [49, 50].

Nanotherapeutic approaches are well explored in the case of cervical, oral and oropharyngeal cancer. Other HPV-related cancers, such as anal cancer, vaginal cancer, penile cancer, and vulvar cancer, are relatively rare, and their treatment approaches are limited to conventional therapies and nanotherapeutics, which have not been much explored in their cases.

Nanoparticle mediated targeted drug delivery in HPV related cancer

For targeted drug delivery, various types of nanoparticles are used, including organic nanoparticles, e.g., liposomes, micelles, dendrimers, etc. inorganic nanoparticles e.g. gold nanoparticles, silica nanoparticles, carbon nanotubes, quantum dots, etc.; hybrid nanoparticles e.g. lipid-polymer hybrid nanoparticles, organic–inorganic hybrids, etc. [44]. Use of these nanoparticles offers significant therapeutic potential by enhancing pharmacological activity, bioavailability, and drug solubility [51] (Fig. 2).

Fig. 2.

Various types of nanoparticles including some organic, inorganic and hybrid types, used in HPV related cancer therapeutics

Liposomes are organic nanoparticles that are widely used as nanocarrier for targeted drug delivery. These consist of concentric bilayers of lipid surrounding an aqueous core and ranging in size from a few nanometres to a few micrometres. These have the ability to encapsulate both lipophilic and hydrophilic substances. It can retain lipophilic agents within the lipid membrane and hydrophilic agents within the aqueous core [52]. By using the “enhanced permeability and retention (EPR) mechanism,” liposomal nanocarriers can improve the pharmacokinetic characteristics of the enclosed drug, lengthen retention times, and enable passive targeting and accumulation in tumours and inflammatory areas [53]. Due to these properties’ liposomes are almost an ideal nanocarrier for drug delivery. Among HPV-related cancers, liposomes are used to deliver anticancer agents such as cisplatin, bleomycin sulfate, curcumin, and mifepristone in cervical cancer (Table 1, Fig. 3) [54–56]. In oral cancer as well, liposome formulations demonstrated effective local delivery and improved therapeutic outcomes (Table 2, Fig. 4) [57]. Dendrimers and micelles are other organic nanomaterials widely used in targeted drug delivery in cancer [44]. Dendrimers are nanoparticles characterized by their radial symmetry and well-defined, uniform, monodisperse structures consisting of a symmetric core, an inner shell, and an outer shell [58]. Micelles are self-assembling colloidal nanoparticles made of amphiphilic surfactants with a hydrophilic shell encircling a hydrophobic core [59]. Targeted drug delivery using dendrimers and micelles has also shown enhanced therapeutic outcomes in HPV-related cancers (Tables 1 and 2) [60, 61]. Inorganic nanoparticles are derived from metals (e.g., gold- or silver-based) or from non-metals (e.g. quantum dots, carbon dots, and carbon nanotubes) [62]. The use of these nanoparticles in HPV-related cancer therapy is summarized in Tables 1 and 2. Moreover, nanoparticles have been engineered to deliver chemotherapeutic agents or siRNA targeting HPV oncogenes (E6/E7) with high specificity. For example, patent WO2021229014A1 describes nanoparticles carrying immunogenic fragments for therapeutic applications [63].

Table 1.

Nanoparticles used in cervical cancer therapeutics

S. No	Type	Nano-carrier	Therapeutic method	Drug/therapeutic agent	Major finding	References
1	Liposome	Liposome	Chemotherapy	Cisplatin & Mifepristone	significantly reduced cell viability and tumor size	[55]
2	Dendrimers	Polyamidoamine (PAMAM)	Chemotherapy	Curcumin	Significantly enhanced cellular uptake of curcumin and tumor cell proliferation inhibition	[93]
3	Hybrid nanoparticles	Hyaluronic acid and 3-mercaptopropionic acid-coated gold NPs conjugated with folic acid (FA-HA-ss-gold/MTX NPs)	Chemotherapy	Methotrexate (MTX)	Enhanced tumor cell targeting and cytotoxicity	[94]
4	Hybrid nanoparticles	Gold nanoparticles (AuNPs), stabilized with the thiol 3-mercapto-propanesulfonate (AuNP-3MPS-MTX)	Chemotherapy	Methotrexate (MTX)	Enhanced cytotoxicity and drug penetration	[95]
5	Dendrimer	Polyamidoamine (PAMAM)	Chemotherapy	3,4-difluorobenzylidene diferuloylmethane (CDF)	Enhanced anticancer activity and targeting in folate receptor overexpressing cancer cells	[60]
6	Metal based	Gold nanoparticles (AuNPs)	Radiotherapy	γ-radiation	Enhance γ-radiation-induced cytotoxicity and ROS production, improving the efficacy of radiotherapy	[96]
7	Inorganic Nanoparticles	Silica-coated gold (Au@SiO2) nanoparticles	Immunotherapy	Antibodies against the scavenger receptor class B type I (SR-BI)	Induce apoptosis and photothermal ablation in cervical cancer cells	[70]
8	Dendrimers	Polyamidoamine (PAMAM)	Gene therapy	Bcl-2 siRNA	Significantly enhanced cellular uptake of curcumin and tumor cell proliferation inhibition	[93]
9	Micelle	Polyion complex (PIC) micelle	Gene Therapy	si16E6/E7 and si18E6/E7	Suppressed tumor growth and restored p53 expression	[97]
10	Polymer based	Acetalated cyclic oligosaccharide & Polyethyleneimine (hybrid ACD nanoparticles)	Gene Therapy	Cas9 mRNA and guide RNAs (gRNAs) targeting E6/E7 oncogenes	Efficiently targeted HPV oncogenes, promoted CD8+ T cell survival, and enhanced antitumor effects	[83]

Fig. 3.

Various nanoparticles used in HPV-related cervical cancer treatment involving chemotherapeutic drug delivery, gene therapy, radiotherapy and immunotherapy, showing positive results

Table 2.

Nanoparticles used in oral and oropharyngeal cancer therapeutics

S. No	Type	Nano-carrier	Therapeutic method	Drug/therapeutic agent	Major finding	References
1	Liposome	Liposome	Chemotherapy	Erlotinib	Sustained release and enhanced anticancer activity, improving tumor reduction in oral cavity cancers	[57]
2	Hybrid nanoparticle	Human serum albumin and Oleanolic acid NPs	Chemotherapy	Doxorubicin	Enhance drug uptake, apoptosis, and cell cycle arrest, showing superior therapeutic effects in both in vitro and in vivo models	[98]
3	Micelles	Polycaprolactone-polyethylene glycol (PCL-PEG) micelles	Chemotherapy	Icaritin	Enhance therapeutic efficacy by improving drug stability, release, and selective delivery to OSCC cells	[61]
4	Metal Based	PEG conjugated AuNP coated with Gadolinium oxide layers	Radiotherapy	X-ray and MR Contrast guided radiotherapy	Enhance radiation therapy by improving tumor imaging and reducing tumor growth and metastasis	[67]
5	Metal based	Gold-coated magnetic core–shell nanoparticles (Fe3O4@Au NPs)	Radiotherapy	X-ray	Enhance treatment efficacy for HPV-positive oropharyngeal cancer by improving cellular uptake and increasing cancer cell apoptosis	[99]
6	Hybrid nanoparticle	Chitosan/tripolyphosphate (CS-TPP)	Gene therapy	MTHFD1L shRNA & 5-aminolevulinic acid	Effectively co-delivers shRNA and photosensitizer, enhancing apoptosis, ROS generation, and anti-tumor effects	[82]

Fig. 4.

This image displays various types of nanoparticles that are used in the treatment of oropharyngeal and oral cancers caused by HPV, which includes gene therapy, radiation therapy, and chemotherapy drug delivery with promising outcomes

Nanoparticle mediated radiotherapy in HPV related cancer

Radiotherapy is one of the most widely used methods for cancer treatment. However, radiotherapy has limitations such as lack of selectivity, resistance to radiation, and tumor recurrence [64]. Thus, coupling radiotherapy with nanotechnology enhances radiosensitivity and therapeutic outcome as compared to radiotherapy alone [64]. Nanomaterials have shown enhanced radiotherapy response by concentrating radiations on particular target cells [47]. Various nanomaterials have been studied as radio-sensitizers and these are reported to enhance radiotherapy effects and overcome radiotherapy resistance. These include metal-based nanoparticles, nonmetal-based nanoparticles and polymer-based nanoparticles [47]. Among metal-based nanoparticles gold-based nanoparticles (AuNPs) are the most extensively studied. These are regarded as excellent radiosensitizers for radiotherapy because of their immense X-ray absorption capability and distinctive physio-chemical characteristics [65].

Recent studies have shown enhanced radiotherapy response and increase apoptosis and cell death to cervical cancer cell lines after treatment with AuNPs [66] (Fig. 3). A recent reported that gold nanoparticle with a gadolinium oxide coating enhances radiotherapy response in head and neck squamous cell carcinoma (HNSCC) models [67]. In phase 1 clinical trial, activated guided irradiation by X-ray (AGuIX) nanoparticles improved MRI precision and radiotherapy efficacy by enhancing tumor-specific accumulation, rapid clearance, excellent local control, and no dose-limiting toxicity in cervical cancer patients [68].

Nanoparticle mediated immunotherapy in HPV related cancer

Immunotherapy is another widely used treatment approach for cancer. However, it has challenges such as low immunogenicity and immunotoxicity. These challenges could be addressed successfully by combining immunotherapy with nanotechnology [69]. For instance, immunotherapy coupled with nanotechnology has shown enhanced precise targeting in cervical cancer with improved therapeutic outcomes. This enhances the efficacy of immunotherapy by stimulating tumor-specific cytotoxic T cells and counteracting immunosuppression in the tumor microenvironment (TME) [69]. Nanocarriers could additionally minimize off-target delivery and guarantee that the therapeutic payload is transported to and maintained at the intended site, thereby reducing the toxicity of immunomodulators. Further a recent study explores the potential of silica-coated gold nanoparticles coupled with antibodies targeting scavenger receptor classB type I as a promising approach for nanoparticle-mediated immunotherapy in cervical cancer. It found that FITC-labeled Au@SiO2-SR-BI nanoparticles specifically bind to SR-BI receptors on cancer cell membranes and induce apoptosis and exhibit photothermal ablation of solid tumors upon activation [70] (Fig. 3). Moreover, in a Phase I trial, AB160, a 160-nm nano-immunoconjugate, demonstrated a favourable safety profile and 36.8% partial response rate in gynaecologic cancers, including cervical cancer. The RP2D (ABX 150 mg/m², BEV 60 mg/m²) showed improved paclitaxel delivery, supporting further clinical investigation [71].

Further, HPV vaccines are an effective option with promising results in HPV-related cancer management [72]. But most of these are prophylactic vaccines that produce neutralizing antibodies against pathogens but lack the ability to eradicate pre-existing tumor cells. Hence, the development of therapeutic vaccines for cervical cancer is imperative. Through the delivery of tumor-specific antigens to the lymphatic system and subsequent stimulation of antigen-presenting cells, therapeutic cancer vaccines seek to elicit robust and long-lasting immune responses [73]. Four fundamental components make up therapeutic cancer vaccines: adjuvants, different formulations, cancer antigens, and delivery systems [74]. Among the innovative strategies, virus-like particles (VLPs) have shown great promise. Patents such as those by the University of Rochester have been instrumental in the development of VLP-based vaccines targeting HPV 16 and 18 [75]. These particles mimic the virus structure without containing viral DNA, eliciting strong immune responses, and enhancing the effectiveness of the vaccines.

Additionally, lipid nanoparticles have emerged as a crucial element in next-generation vaccine development. Advances in lipid nanoparticle formulations have significantly improved antigen stability and delivery efficiency, ensuring better targeting of HPV-related tumors. Nanoscale adjuvants and delivery vehicles are used in therapeutic vaccines and have been reported to enhance the cytotoxicity of these vaccines against cervical cancer [74]. These innovations offer a more targeted and effective approach to treating HPV-related cancers, moving beyond mere prevention to actively combating pre-existing cancer cells.

Nanoparticle mediated gene therapy in HPV related cancer

Gene therapy has several advantages over traditional treatments for cancer, such as increased specificity, reduced toxicity, precise targeting, and better therapeutic outcomes. Between different delivery systems for gene therapy, nanoparticles have gained significant interest as gene delivery systems due to several advantages, including low toxicity, precise delivery, high efficiency, etc. [76]. Nanoparticle-mediated gene therapy has emerged as an effective and novel strategy for the treatment of different cancers such as breast cancer [77], retinoblastoma [78], lung cancer [79], and colon cancer [80]. Numerous nanoparticle types, including inorganic, polymeric, and lipid-based nanoparticles, are being researched for the delivery of cancer genes, including [76].

Among HPV-related cancers, nanoparticle-mediated gene therapy is being explored in cervical cancer [81] and oral cancer [82]. A recent study showed that hybrid pH-responsive nanoparticles effectively deliver CRISPR/Cas9 components targeting HPV oncogenes in cervical cancer cells, showing precise genome editing with minimal off-target effects [83]. In another study on oral cancer, it is reported that nanoparticles combining chitosan/tripolyphosphate (CS-TPP) effectively co-delivered MTHFD1L shRNA and ALA-PDT, thus enhancing cytotoxicity against oral squamous cell carcinoma (OSCC) cells with notable pro-apoptotic and anti-tumorigenesis effects both in vitro and in vivo [82] (Fig. 4). Nanoparticle-mediated delivery of CRISPR/Cas9 targeting HPV oncogenes has shown promising therapeutic results in different studies. For example, a study reported that a self-assembled pH-sensitive cationic nanoliposome effectively delivers CRISPR/Cas9 to target HPV16-positive cervical cancer cells and inhibits tumor growth via gene knockout without significant toxicity in vivo [84]. Similarly, in a cervical cancer model, systemic delivery of CRISPR/Cas9 using PEGylated liposomes was found to effectively eliminate tumors and ensure complete survival in treated animals [85] (Fig. 3).

Nanoparticle-based sensors for HPV detection

The current diagnostic methods for HPV include the Pap smear test, which has a false negative rate ranging from 13 to 70% and a false positive rate between 0 and 14%. Advanced techniques such as microarrays, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and next-generation sequencing (NGS) offer high specificity and sensitivity but are expensive and time-intensive [86].

A recently developed colorimetric nano-sensor has shown promise in detecting high-risk HPV variants 16 and 18. Clinical evaluation demonstrated high specificity, with 77.8% for HPV16 and 87.3% for HPV18, along with excellent negative predictive values exceeding 96%. However, its sensitivity was limited due to the low prevalence of positive samples. This limitation could potentially be addressed by optimizing sample collection methods or enhancing signal amplification techniques. Despite this, the nano-sensor’s simplicity and rapid detection make it a promising tool for HPV screening, especially in resource-limited settings [87].

Another study developed porous silicon (PSi) biosensors for detecting high-risk HPV types 16 and 18, which are commonly linked to pre-cancerous and cancerous lesions. PSi, known for its biocompatibility and unique optical properties, was modified with HPV-specific ssDNA oligonucleotides using amino-silane and glutaraldehyde chemistry. The biosensor's performance was monitored using FTIR and SEM, ensuring the stability and reliability of the device. The molecular binding was optically detected through shifts in the reflectance spectra, which were directly related to biomolecule concentration. The PSi biosensor effectively discriminated between complementary and non-complementary DNA, showing promise for use in portable HPV detection devices. Furthermore, Rasouli et al., 2023, developed a label-free biosensor using Fe₃O₄-Au core–shell nanoparticles on screen-printed carbon electrodes which shows potential for HPV-16 detection. The sensor, functionalized with ssDNA probes, demonstrated high sensitivity with a detection limit of 0.1 nM, making it a promising tool for rapid and accurate HPV diagnostics [88]. Another novel paper-based electrochemical biosensor has been developed for detecting HPV-16, using an anthraquinone-labeled PNA probe and a graphene-polyaniline modified electrode. It achieved a detection limit of 2.3 nM and a linear range of 10–200 nM. Its low cost and disposable design make it a promising tool for early HPV screening [89].

Challenges

Nanoparticles offer specific benefits for cancer treatment, including decreased toxicity and improved stability, biocompatibility, enhanced permeability and retention effect, and accurate targeting [42]. Many in vivo as well as in vitro studies have shown promising results of nanotherapeutics in HPV-related cancers. However, these studies are mostly limited to laboratory or clinical trial stages, presenting a key challenge in translating these findings into clinical practice.

The development of nanotherapeutics has biological hurdles as well as technological hurdles. Biological hurdles include limited administration routes, biological barriers, their degradation, and toxicity. Technological obstacles related to nanoparticles include large-scale synthesis optimization, low costs, and good repeatability [42]. Biological barriers in nanotherapeutics arise due to interactions of nanomaterials with bio-barriers (e.g., complement system and tumor interstitial tissues), limited effectiveness of passive targeting approaches, and potential nanotoxicity [90]. Among technological hurdles, large-scale production of nanoparticles is affected due to complex nanoplatforms.

A strong regulatory framework is crucial for ensuring the safety and efficacy of nanomedicines. Because of their small size and unique properties, nanomaterials can interact with biological systems and could lead to toxicity, self-assembly of nanoparticles and other unintended side effects. The toxicity of nanotherapeutics affects multiple biological systems, causing oxidative stress, inflammation, DNA damage, and potential carcinogenicity. Understanding these effects through advanced models like 3D organoids is crucial for evaluating their safety and therapeutic viability [91]. Further, regulatory challenges in developing nanotherapeutics for HPV-related cancers stem from the complexity of these cancers, including their genetic diversity and immune evasion mechanisms. There’s also a lack of standardized guidelines for nanoparticle testing, which makes it challenging to assess safety and effectiveness. Moreover, production of nanomedicine is highly sensitive to small changes in synthesis conditions, leading to batch-to-batch inconsistencies [92]. Therefore, it is essential to establish clearer regulatory guidelines and standardized testing methods, to ensure reliability and consistency in development of nanotherapeutics for HPV-related cancers.

Conclusion and future prospect

HPV is a major factor in causing cancer, plus it is among the most widespread causes of STIs, affecting a large portion of the adult population. Conventional treatment methods for HPV-related cancers include surgery, chemotherapy, and radiotherapy. One of the major challenges in conventional therapy is preserving fertility in surgeries primarily for cancer localized in the genital region. Additionally, the conventional therapies currently in use are non-specific, and they come with adverse side effects. Therefore, targeted therapies, including nanotherapies, are key to overcoming the adverse effects. Nanotherapeutics has revolutionised cancer treatment, current study highlights various nanoparticle-mediated HPV-related cancer trials that have shown promising results. Nanoparticles offer a promising approach for targeted drug delivery in HPV-related cancers by enhancing drug solubility, bioavailability, and therapeutic efficacy. Further nanoparticles could be aided with radiation therapy to enhance radiosensitivity and therapeutic efficacy in cancer treatment, particularly in cervical and head and neck cancers. Moreover, nanotherapeutics can also incorporate emerging treatment approaches, such as immunotherapy or gene therapy, to enhance therapeutic outcomes.

However, there is a need for more clinical trials to further validate these findings, ensuring the safety and efficacy of nanoparticle-mediated therapies in HPV-related cancers. Additionally, there’s a need to explore strategies to improve the effectiveness of passive targeting methods like the EPR effect and mitigate potential nanotoxicity which refers to the toxicity caused by nanoparticles. Furthermore, research should focus on simplifying complex nanoplatforms to enable large-scale production with low costs and high repeatability, thereby facilitating their clinical translation and enhancing the impact in HPV-related cancer treatments. Another challenge is the variability in patient-specific tumor microenvironments, which can influence nanoparticle accumulation and therapeutic response. Additionally, regulatory hurdles and long-term biosafety concerns must be addressed to ensure clinical approval and widespread adoption.

Author contributions

US, HS, BS: writing original draft and literature search; AS: literature search and editing; preparation of figures. SH, DMM, DK, HST & AM: literature search, review & editing, and preparation of tables; FA: conceptualisation and review and editing.

Funding

The authors have no source of funding.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

It’s a review article. So, no ethical approval and no consent from participants is required.

Consent for publication

All the authors read and approved the final version of the manuscript. The authors do not want open access to the manuscript. Therefore, we assure you that this manuscript was not send for publication in any other journal.

Competing interests

The authors declare no competing interests.