1.INTRODUCTION:

Overview of Chemotherapy Resistance:

Chemotherapy remains one of the cornerstone treatments for cancer, yet the emergence of drug resistance often compromises its effectiveness. Chemotherapy resistance refers to the ability of cancer cells to survive and proliferate despite the administration of chemotherapeutic agents. This phenomenon is a significant cause of treatment failure, leading to cancer relapse and poor patient outcomes¹. Studies estimate that drug resistance accounts for over 90% of cancer-related mortality, particularly in advanced and metastatic stages. Resistance can be classified as either intrinsic, where cancer cells possess pre-existing resistance mechanisms, or acquired, where cells adapt in response to prolonged drug exposure².

Mechanisms of chemotherapy resistance are multifaceted, involving genetic mutations, epigenetic modifications, alterations in drug transport, and activation of survival signalling pathways. Traditionally, factors such as efflux pump overexpression, enhanced DNA repair, and apoptotic evasion have been recognised as primary contributors³. However, recent advances have uncovered the pivotal role of extracellular vesicles (EVs) in mediating resistance, shifting the paradigm of how cancer cells communicate and adapt within the tumour microenvironment^4–6.

1.1. Extracellular Vesicles (EVs)- An Emerging Player:

Extracellular vesicles are membrane-bound structures secreted by almost all cell types, including cancer cells, and play a crucial role in intercellular communication. These vesicles transport bioactive molecules, including proteins, lipids, RNA, and DNA, facilitating various physiological and pathological processes⁷. EVs are broadly classified into three main types based on their size, biogenesis, and composition:

1. Exosomes (30–150nm): These small vesicles originate from the endosomal system and are released upon the fusion of multivesicular bodies with the plasma membrane. Exosomes are highly enriched in specific markers such as CD63, CD81, and CD9, and their cargo reflects the molecular signature of their originating cells⁸.

2. Microvesicles (100–1,000nm): Microvesicles, formed by direct budding from the plasma membrane, actively contribute to shaping the tumour microenvironment. Unlike exosomes, they are more heterogeneous in content and size, facilitating the horizontal transfer of drug resistance traits^9,10.

3. Apoptotic Bodies (>1,000nm): These vesicles are produced during programmed cell death and contain nuclear fragments, organelles, and cytoplasmic content. While primarily associated with cell clearance, apoptotic bodies can also contribute to resistance by transferring survival signals to neighbouring cells¹¹.

EV secretion is tightly regulated through complex intracellular pathways involving the ESCRT (endosomal sorting complexes required for transport) machinery, lipid raft-mediated sorting, and Rab GTPases. Cancer cells exploit these mechanisms to enhance EV secretion, thereby enriching the tumour microenvironment with factors that promote survival and resistance¹².

Figure 1. Extracellular Vesicle Biogenesis, Secretion, and Uptake Pathways¹³

1.2. EVs in Cancer Progression and Drug Resistance:

A growing body of evidence has established EVs as key mediators in cancer progression, metastasis, and drug resistance. These vesicles serve as messengers, transferring oncogenic signals between cancerous and stromal cells, thereby remodelling the tumour microenvironment in favour of malignancy^14,15.

Recent studies have demonstrated that EVs derived from drug-resistant cancer cells can transfer resistance-related molecules to drug-sensitive cells, conferring resistance through multiple mechanisms. For example, in breast cancer, exosomes enriched with P-glycoprotein (P-gp), a well-known drug efflux transporter, have been shown to induce resistance in previously sensitive cells. Similarly, in glioblastoma, EVs containing miR-1238 and other microRNAs have been implicated in the modulation of key drug-resistance pathways, reducing the efficacy of temozolomide therapy^16,17.

Beyond direct molecular transfer, EVs play a critical role in immune evasion by suppressing anti-tumour immune responses. Cancer-derived EVs can carry PD-L1, a well-established immune checkpoint inhibitor, leading to T-cell dysfunction and enabling tumour survival despite chemotherapy¹⁸. Additionally, EV-mediated remodelling of the extracellular matrix (ECM) facilitates metastatic dissemination, further complicating treatment strategies¹⁹.

Moreover, EV cargo composition is highly dynamic and can be influenced by chemotherapeutic stress. Studies have revealed that exposure to chemotherapeutic agents induces a selective enrichment of resistance-associated proteins and RNAs in EVs. This adaptive response enables tumours to evolve rapidly and survive under drug pressure. For instance, in pancreatic cancer, EVs carrying high levels of Snail and Twist, key regulators of epithelial-mesenchymal transition (EMT), have been implicated in enhanced invasiveness and chemoresistance²⁰.

The recognition of extracellular vesicles as central players in chemotherapy resistance has revolutionised our understanding of tumour adaptability. By facilitating the intercellular transfer of drug resistance determinants, EVs contribute to the dynamic and multifactorial nature of cancer progression²¹. Unravelling the mechanisms by which EVs mediate resistance will not only enhance our ability to predict and monitor therapeutic outcomes but also provide novel avenues for intervention. As research continues, targeting EV biogenesis, secretion, and uptake presents a promising strategy to overcome drug resistance and improve the efficacy of chemotherapy in cancer treatment^6,22,23.

2. Mechanisms: How Tumour-Derived EVs Induce Chemotherapy Resistance:

The ability of cancer cells to resist chemotherapy is primarily influenced by extracellular vesicles (EVs), which facilitate intercellular communication and adaptative survival mechanisms. Tumour-derived EVs carry bioactive cargo, including ATP-binding cassette (ABC) transporters, microRNAs (miRNAs), proteins, and long non-coding RNAs (lncRNAs), which collectively contribute to drug efflux, apoptosis resistance, tumour microenvironment (TME) remodelling, and the horizontal transfer of resistance traits. These mechanisms establish a dynamic network that supports multidrug resistance (MDR), reducing chemotherapy efficacy and leading to treatment failure²⁴.

2.1. EV-Mediated Drug Efflux Mechanisms- EVs Carrying ABC Transporters:

One of the primary mechanisms by which EVs confer drug resistance is the transfer of ABC transporters, a family of efflux proteins responsible for expelling chemotherapeutic agents from cancer cells²⁵. Among the most notable are:

· P-glycoprotein (P-gp/ABCB1/MDR1): An extensively studied efflux transporter that pumps out various chemotherapeutic drugs, such as paclitaxel, doxorubicin, and vincristine. Studies have shown that EVs derived from drug-resistant cells can transfer functional P-gp to sensitive cells, inducing resistance²⁶.

· Multidrug Resistance Protein 1 (MRP1/ABCC1): Responsible for the efflux of organic anions and hydrophobic drugs, such as cisplatin and etoposide. Tumour-derived EVs carrying MRP1 contribute to the reduced intracellular accumulation of drugs, leading to treatment failure²⁷.

· Breast Cancer Resistance Protein (BCRP/ABCG2): Associated with resistance to mitoxantrone, topotecan, and methotrexate, BCRP-containing EVs enhance drug efflux and chemoresistance in various cancers, including breast and ovarian cancer^28,29.

The presence of these transporters in EVs creates a bystander effect, where non-resistant cancer cells acquire resistance through protein transfer, ultimately propagating MDR within the tumour.

Figure 2. Role of Tumour-Derived Exosomes in Mediating Chemotherapy Resistance³⁰

2.2. EV Cargo Modulating Apoptosis Resistance- miRNAs and Apoptotic Proteins:

Apoptosis, or programmed cell death, is a critical mechanism targeted by chemotherapy to eliminate cancer cells³¹. However, tumour-derived EVs actively suppress apoptotic signalling, allowing cancer cells to evade cell death³². Key miRNAs and proteins transported via EVs contribute to this resistance:

· miR-21 and miR-155: These oncogenic miRNAs, encapsulated within EVs, downregulate pro-apoptotic genes such as PTEN, PDCD4, and BAX, preventing apoptosis in tumour cells post-chemotherapy³³.

· Caspase-3 (CASP3) Suppression: EVs from drug-resistant cancer cells carry miRNAs that inhibit CASP3, a key executioner of apoptosis, further promoting cell survival³⁴.

As a result, chemotherapy-induced apoptosis is significantly impaired, allowing cancer cells to persist and repopulate even in the presence of cytotoxic agents.

2.3 EVs Remodeling the Tumour Microenvironment (TME):

1) Fibroblast Activation & ECM Stiffening: The tumour microenvironment plays a vital role in chemoresistance, with cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) remodelling acting as protective barriers against therapy³⁵. Tumour-derived EVs facilitate this remodelling by delivering:

· Transforming Growth Factor-Beta (TGF-β): Induces the activation of fibroblasts into CAFs, which secrete pro-survival factors that enhance tumour resistance.

· Matrix Metalloproteinases (MMPs): Promote ECM degradation and remodelling, allowing for increased tumour invasiveness and survival.

· Interleukin-6 (IL-6): Stimulates a pro-inflammatory environment that supports cancer cell proliferation and protects against chemotherapeutic agents.

These EV-mediated alterations create a stiffened ECM and a supportive niche for cancer cells, reducing drug penetration and enhancing survival post-chemotherapy^36–38.

2) Immunosuppressive EV Cargo: Beyond physical protection, tumour-derived EVs also suppress anti-tumour immune responses, further diminishing chemotherapy effectiveness:

· PD-L1-Expressing EVs: Tumour cells release EVs carrying programmed death-ligand 1 (PD-L1), which binds to PD-1 on T-cells, inhibiting their cytotoxic function and allowing immune evasion.

· Regulatory T Cell (Treg)-Promoting EVs: EVs carrying immunosuppressive factors promote Treg expansion, which dampens immune-mediated tumour clearance and supports a chemo-resistant microenvironment.

These immune-modulating EVs contribute to a highly adaptive, therapy-resistant tumour landscape^39–41.

2.4. EV-Mediated Horizontal Transfer of Resistance Factors:

1) Transfer of Resistance Proteins: EVs serve as vehicles for the horizontal transfer of resistance-related proteins, allowing previously drug-sensitive cells to adopt resistance mechanisms. Notable proteins transferred via EVs include:

· Bcl-2 and Surviving: Anti-apoptotic proteins that inhibit cell death pathways, sustaining tumour survival despite chemotherapy.

· Hypoxia-Inducible Factor 1-Alpha (HIF-1α): Promotes adaptation to hypoxic conditions and induces metabolic reprogramming, enhancing resistance to various chemotherapeutic agents.

By disseminating these survival-promoting factors, EVs facilitate widespread resistance across tumour populations^42,43.

2) Role of Long Non-Coding RNAs (lncRNAs) and Circular RNAs (circRNAs): EVs also transfer non-coding RNAs that regulate gene expression and epigenetic modifications associated with drug resistance. Key examples include:

· lncRNA-PVT1: lncRNA-PVT1, present in extracellular vesicles from doxorubicin-resistant cancer cells, regulates drug metabolism and activates survival pathways.

· circRNA-002178: Implicated in cisplatin resistance, this circular RNA enhances oncogenic signalling, thereby diminishing drug efficacy.

Through the dissemination of these regulatory RNAs, EVs enable tumours to adapt and develop resistance rapidly to diverse chemotherapeutic agents^44,45.

Extracellular vesicles play a multifaceted role in chemotherapy resistance, mediating drug efflux, apoptosis evasion, tumour microenvironment remodelling, and the horizontal transfer of resistance factors. By acting as molecular messengers, EVs create a highly adaptive and resilient tumour landscape that undermines therapeutic efficacy. Understanding these EV-driven mechanisms opens new avenues for therapeutic interventions aimed at disrupting EV biogenesis, uptake, and cargo transfer, offering promising strategies to counteract drug resistance in cancer treatment^46,47.

3. Clinical Implications: EVs as Biomarkers and Therapeutic Targets:

The growing recognition of extracellular vesicles (EVs) as critical mediators of chemotherapy resistance has led to significant interest in their clinical applications. EVs serve as both biomarkers for predicting resistance and potential therapeutic targets for overcoming drug insensitivity. Their presence in body fluids such as blood, urine, and saliva make them accessible for liquid biopsy-based diagnostics. At the same time, their unique cargo composition offers opportunities for targeted interventions. This section explores the potential of EVs in precision oncology, focusing on their roles as biomarkers and their therapeutic targeting to reverse resistance⁴⁸.

3.1. EVs as Biomarkers for Predicting Chemotherapy Resistance:

1) Liquid Biopsy Applications: Liquid biopsies, which involve the analysis of circulating tumour-derived components in body fluids, offer a non-invasive alternative to traditional tissue biopsies⁴⁹. EVs play a crucial role in this approach by carrying molecular markers that reflect the dynamic tumour landscape⁵⁰. Notably, EV-derived microRNAs (miRNAs) and DNA mutations serve as promising indicators of chemotherapy resistance.

· EV-miRNA Panels: Several miRNAs encapsulated in plasma-derived EVs have been identified as predictive biomarkers of drug resistance. For instance, miR-192, miR-484, and miR-205 have been implicated in resistance to platinum-based chemotherapy in ovarian and lung cancers. The detection of these miRNAs in circulating EVs provides early warning of treatment failure, enabling timely therapeutic adjustments⁵¹.

· EV-DNA Mutations: Tumour-derived EVs also contain fragmented DNA that mirrors the genomic alterations of their parent cells. Mutations in KRAS, TP53, and EGFR, frequently found in EVs from lung and colorectal cancer patients, correlate with resistance to targeted therapies such as EGFR inhibitors. The ability to monitor these genetic changes in real time enhances personalised treatment approaches⁵².

Table 1. EV Biomarkers in Different Cancers

Cancer Type	EV Biomarkers	Cargo Type	Function in Cancer Progression
Breast Cancer	miR-21, miR-155, HER2	miRNA, Protein	Promotes metastasis, drug resistance
Lung Cancer	miR-486, ALIX, TSG101	miRNA, Protein	Tumor progression, immune evasion
Colorectal Cancer	KRAS, miR-92a	Protein, miRNA	Enhances proliferation, chemoresistance
Pancreatic Cancer	GPC1+, miR-196a	Protein, miRNA	Biomarker for early detection
Glioblastoma	EGFRvIII, miR-21	Protein, miRNA	Induces angiogenesis, tumor invasion

2) Exosomal Protein Signatures: In addition to nucleic acids, EVs carry a diverse range of proteins that can serve as predictive biomarkers for chemotherapy response⁵³.

· PD-L1 in EVs: The presence of programmed death-ligand 1 (PD-L1) in circulating EVs has been shown to predict responses to immune checkpoint inhibitors such as anti-PD-1 therapy. Elevated levels of EV-PD-L1 correlate with resistance to checkpoint blockade therapies, as they contribute to immune evasion by inhibiting T-cell activation⁵⁴.

· Drug Transporter Proteins: EVs enriched with ATP-binding cassette (ABC) transporters, including P-gp and MRP1, serve as indicators of multidrug resistance (MDR)⁵⁵. Their detection in patient plasma can provide early insights into emerging chemoresistance, aiding treatment modification strategies⁵⁶.

These findings highlight the utility of EVs as liquid biopsy markers, offering real-time insights into tumour evolution and drug resistance. The integration of EV-based diagnostics into clinical workflows holds promise for improving chemotherapy outcomes through personalised medicine.

3.2. Targeting EVs to Reverse Chemotherapy Resistance:

Given their central role in drug resistance, EVs have emerged as promising therapeutic targets. Strategies to inhibit EV secretion, neutralise their cargo, or repurpose them for drug delivery are being actively explored to enhance chemotherapy efficacy³⁰.

1) EV Inhibition Strategies: Blocking EV secretion is a direct approach to preventing the spread of resistance factors within the tumour microenvironment⁵⁷. Several pharmacological inhibitors have been developed to disrupt EV biogenesis and release:

· GW4869: An inhibitor of neutral sphingomyelinase 2 (nSMase2), GW4869 prevents the formation of ceramide, a lipid required for exosome biogenesis. This inhibition reduces the release of drug-resistant EVs, enhancing chemotherapy sensitivity.

· Calpeptin: A calpain inhibitor that impairs microvesicle shedding by disrupting cytoskeletal rearrangements. By limiting the secretion of resistance-conferring EVs, calpeptin improves chemotherapy efficacy.

· Rab27a Inhibitors: Rab27a is a key regulator of exosome secretion. Small-molecule inhibitors Targeting Rab27a function reduce exosome-mediated drug resistance in several cancers, including breast and pancreatic cancer.

· Neutralising Antibodies: Neutralising antibodies that target EV surface proteins can prevent EV uptake by recipient cells, thereby blocking the horizontal transfer of resistance factors. This approach has shown promise in preclinical models of MDR.

These EV-targeting strategies hold significant potential for restoring chemotherapy sensitivity in resistant tumours^58–62.

Table 2. Therapy Approach Target Clinical Trial Phase Mechanism

Therapy Approach	Target	Clinical Trial Phase	Mechanism
EV-based Drug Delivery	Doxorubicin-loaded EVs	Phase II	Enhances drug targeting, reduces toxicity
Blocking EV Biogenesis	GW4869 (nSMase inhibitor)	Preclinical	Inhibits exosome secretion
EV Surface Targeting	Anti-CD63 antibodies	Phase I	Prevents EV uptake by recipient cells
EV-based Immunotherapy	PD-L1+ EV inhibitors	Phase II	Enhances anti-tumor immune response
Engineered EV Therapy	miR-loaded EVs	Preclinical	Delivers tumor-suppressive miRNAs

2) Engineered EVs for Drug Delivery: Beyond inhibition, EVs can be harnessed as drug carriers for targeted therapy. Their natural biocompatibility and ability to cross biological barriers make them ideal vehicles for delivering chemotherapeutic agents or gene-editing tools to drug-resistant tumours^63,64.

· EV-Loaded Chemotherapy Drugs: Engineering EVs to encapsulate chemotherapeutic agents, such as doxorubicin or paclitaxel, enhances targeted drug delivery while reducing systemic toxicity. Preclinical studies have demonstrated that exosome-mediated drug delivery increases drug accumulation in resistant tumour cells, overcoming MDR.

· CRISPR-Based EV Therapy: EVs can be loaded with CRISPR/Cas9 components to silence resistance-associated genes selectively. For example, CRISPR-loaded EVs targeting MDR1 (ABCB1) have been shown to restore drug sensitivity in resistant cancer models by suppressing P-gp expression.

These novel applications underscore the dual potential of EVs in both diagnostics and therapeutics, paving the way for next-generation precision oncology strategies^65–67.

Extracellular vesicles represent a groundbreaking frontier in cancer research, serving as both biomarkers and therapeutic targets in chemotherapy resistance. The ability to detect EV-encapsulated nucleic acids and proteins through liquid biopsy offers a non-invasive approach to predicting treatment responses and monitoring tumour evolution⁶⁸. Additionally, strategies aimed at inhibiting EV secretion or repurposing them for targeted drug delivery hold immense promise for reversing resistance and improving patient outcomes. As research progresses, integrating EV-based technologies into clinical practice could revolutionise personalised cancer treatment, offering new hope for overcoming chemotherapy resistance⁶⁹.

4. Challenges, Open Questions, and Future Perspectives:

Despite the growing body of evidence supporting the role of extracellular vesicles (EVs) in chemotherapy resistance, translating these findings into clinical applications presents several challenges. EV-based therapeutics face hurdles related to heterogeneity, isolation, and potential unintended consequences. Moreover, many unanswered questions remain regarding their precise role in drug resistance, particularly in the context of evolving treatment strategies such as immunotherapy-chemotherapy combinations. Addressing these challenges and research gaps will be essential for harnessing EVs in precision oncology.

4.1. Challenges in EV-Based Therapeutics:

1) EV Heterogeneity and Isolation Difficulties: One of the fundamental challenges in EV-based therapeutics is the inherent heterogeneity of EV populations. EVs vary in size, composition, and function, making it challenging to define standardised biomarkers or therapeutic targets⁷⁰. Additionally, tumour-derived EVs are often mixed with EVs from normal cells in circulation, complicating their selective isolation for clinical applications. Current isolation techniques, including ultracentrifugation, size-exclusion chromatography, and immunoaffinity capture, lack reproducibility and scalability for routine clinical use. Advances in microfluidics and nanotechnology-based separation methods may offer improved solutions, but standardisation remains a critical challenge^71,72.

2) Lack of Standardised Clinical Protocols: While EVs show great promise in liquid biopsy and drug delivery, their clinical translation is hindered by the absence of standardised protocols for characterisation, quantification, and functional validation⁷³. Unlike conventional biomarkers such as circulating tumour DNA (ctDNA) or proteins, EV-based biomarkers lack universally accepted reference materials and cutoff thresholds for diagnostic or prognostic use. Establishing regulatory guidelines for EV-based diagnostics will be essential to enable their integration into clinical workflows⁷⁴.

3) Potential Off-Target Effects of EV-Targeting Drugs: Targeting EV secretion or uptake presents another major challenge, as EVs also play crucial roles in normal physiological processes such as immune regulation, tissue repair, and homeostasis. Broad inhibition of extracellular vesicle (EV) pathways, such as targeting Rab27a or neutral sphingomyelinase 2 (nSMase2), may disrupt critical intercellular communication, potentially causing unintended side effects⁷⁵. Developing tumour-specific EV inhibitors remains a significant challenge, necessitating a deeper understanding of cancer-specific EV biogenesis and uptake mechanisms⁷⁶.

4.2. Open Research Questions:

1) Can We Develop Tumour-Specific EV Inhibitors Without Affecting Normal Cell EVs?

A critical question in EV-targeted therapy is whether tumour-specific inhibitors can be designed to block cancer-derived EVs while selectively preserving normal physiological EV functions⁷⁷. Current inhibitors, such as GW4869 and Rab27a-targeting drugs, have broad effects on EV secretion across all cell types. Identifying tumour-exclusive EV markers or biogenesis pathways could enable the development of more selective inhibitors, reducing the risk of systemic side effects⁷⁸.

2) How Can AI and Nanotechnology Optimize EV-Based Biomarker Identification?

The integration of artificial intelligence (AI) and nanotechnology holds significant promise in refining EV-based biomarker discovery. AI-driven machine learning algorithms can analyse large datasets of EV-derived nucleic acids and proteins to identify predictive resistance signatures with greater precision^79,80. Meanwhile, nanotechnology-based biosensors and lab-on-a-chip platforms could facilitate real-time, high-throughput detection of EV biomarkers in patient samples. The convergence of these technologies could accelerate the clinical adoption of EV-based diagnostics⁸¹.

3) What Is the Role of EV-Mediated Resistance in Immunotherapy-Chemotherapy Combinations?

The interplay between EV-mediated chemotherapy resistance and immune evasion remains poorly understood, particularly in the context of combination therapies involving chemotherapy and immune checkpoint inhibitors. Emerging evidence suggests that EVs carrying PD-L1 can contribute to immune suppression, potentially undermining the efficacy of immunotherapy⁸². Investigating the dual role of EVs in both chemotherapy and immune resistance could reveal novel therapeutic targets for overcoming treatment failure in combination regimens⁸³.

4.3. Future Directions:

1) Integration of EV-Based Biomarkers in Clinical Trials for Personalised Chemotherapy Regimens:

To fully realise the potential of EV-based diagnostics, future clinical trials should incorporate EV-derived biomarkers as predictive tools for tailoring chemotherapy regimens. Stratifying patients based on EV cargo signatures—such as miRNA panels (miR-192, miR-484, miR-205) or EV-DNA mutations (KRAS, TP53, EGFR)—could enable more personalised treatment approaches, improving response rates while minimising unnecessary toxicity^84,85.

2) Development of Synthetic EV-Mimetic Nanoparticles to Disrupt Resistance Pathways:

An emerging strategy to counteract EV-mediated drug resistance involves the design of synthetic EV-mimetic nanoparticles. These engineered vesicles can either act as decoys to sequester resistance-related EV cargo or deliver targeted therapies that disrupt resistance mechanisms. For example, synthetic vesicles functionalised with receptors for P-glycoprotein (P-gp) could serve as molecular sponges to neutralise drug efflux proteins before they reach recipient cells^86,87.

3) EV-Based Delivery of siRNA and Gene Editing Tools:

The ability of EVs to efficiently transport nucleic acids has spurred interest in using them to deliver small interfering RNA (siRNA) and gene-editing tools such as CRISPR/Cas9. Engineering EVs to selectively deliver siRNA-targeting resistance genes—such as MDR1 (ABCB1) or Bcl-2—could offer a particular approach to overcoming drug resistance. Similarly, CRISPR-loaded EVs could be used to knock out resistance-associated genes in tumour cells, restoring chemosensitivity while minimising off-target genetic alterations^88,89.

5. CONCLUSION:

Extracellular vesicles (EVs) have emerged as key mediators of chemotherapy resistance, playing crucial roles in drug efflux, apoptosis inhibition, tumour microenvironment remodelling, and horizontal transfer of resistance factors. Through the transfer of ATP-binding cassette (ABC) transporters, anti-apoptotic proteins, and regulatory RNAs, EVs facilitate intercellular communication that promotes tumour survival and multidrug resistance. Their involvement in immune evasion further complicates chemotherapy efficacy, underscoring their importance in cancer progression.

Clinically, EVs hold immense potential as biomarkers for predicting chemotherapy resistance. Liquid biopsy-based detection of EV-encapsulated miRNAs (e.g., miR-192, miR-484, miR-205), oncogenic DNA mutations (KRAS, TP53, EGFR), and protein signatures (PD-L1, P-gp) offers a non-invasive method for monitoring treatment response and guiding therapeutic decisions. Furthermore, targeting EV biogenesis and uptake using inhibitors such as GW4869, Rab27a blockers, or neutralising antibodies represents a promising strategy for reversing resistance. The engineering of EVs for drug delivery, particularly CRISPR-based EVs for gene silencing of resistance pathways, introduces new avenues for precision medicine.

However, several challenges must be addressed before EV-based diagnostics and therapeutics can be fully integrated into clinical practice. EV heterogeneity, lack of standardised isolation protocols, and potential off-target effects of EV-targeting drugs remain significant obstacles. Open research questions, including the development of tumour-specific EV inhibitors and the application of AI-driven biomarker identification, must be further explored.

Looking ahead, the integration of EV-based biomarkers in clinical trials, the development of synthetic EV-mimetic nanoparticles, and the use of EVs for gene therapy represent promising directions. With continued advancements, EV-targeted strategies have the potential to revolutionise cancer treatment, offering novel solutions to overcome chemotherapy resistance and improve patient outcomes in the era of personalised oncology.

6. CONFLICT OF INTEREST:

The authors declare that there is no conflict of interest regarding the publication of this article.

7. ACKNOWLEDGEMENTS:

The authors would like to express their sincere gratitude to Avinash B. Darekar, Principal, K. V. N. Naik S. P. Sanstha’s Institute of Pharmaceutical Education & Research, Nashik, Maharashtra, for his continuous support and encouragement throughout the course of this work.

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Received on 05.06.2025 Revised on 08.07.2025

Accepted on 05.08.2025 Published on 04.10.2025

Available online from October 10, 2025

Asian J. Res. Pharm. Sci. 2025; 15(4):371-380.

DOI: 10.52711/2231-5659.2025.00055

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