Exosome-based therapy and targeted PROTAC delivery: A new nanomedicine frontier for HPV-mediated cervical cancer treatment

Human papillomavirus (HPV) is a significant aetiological agent in cervical cancer, leading to a considerable burden of disease worldwide.¹ The persistence of high-risk HPV types results in the expression of oncoproteins E6 and E7, which disrupt key tumour suppressor pathways.² Traditional treatment modalities for cervical cancer, such as surgery, chemotherapy and radiation, often come with substantial side effects and limitations.³ Emerging therapies, including exosome-based delivery systems and Proteolysis Targeting Chimeras (PROTACs), offer promising new avenues for targeted molecular medicine.^4-6 Exosomes, in particular, have garnered attention due to their natural biocompatibility, ability to target specific cells and capacity to protect therapeutic cargo from degradation, making them an ideal vehicle for PROTAC delivery.^{7, 8}

Exosomes are small extracellular vesicles (30–150 nm) secreted by various cell types into bodily fluids such as blood, urine and saliva.⁹ These vesicles are formed through the inward budding of the endosomal membrane, creating multivesicular bodies that fuse with the plasma membrane to release exosomes into the extracellular environment. Exosomes carry a diverse array of biomolecules, including proteins, lipids and RNAs, reflective of their cell of origin.¹⁰ This intrinsic characteristic enables exosomes to act as natural delivery vehicles for therapeutic agents. Furthermore, exosomes exhibit low immunogenicity and can be engineered to display specific ligands on their surface, facilitating targeted delivery to particular cell types, such as HPV-infected or cervical cancer cells.

PROTACs represent a novel class of therapeutic agents designed to induce the degradation of specific target proteins by harnessing the cellular ubiquitin-proteasome system. A PROTAC molecule consists of two ligands connected by a linker: one ligand binds to the target protein, while the other recruits an E3 ubiquitin ligase. This proximity leads to the ubiquitination and subsequent proteasomal degradation of the target protein.^{10, 11} PROTACs offer several advantages over traditional small molecule inhibitors, including the ability to target proteins previously considered ‘undruggable,’ a reduced likelihood of drug resistance, and the potential for complete elimination of pathogenic proteins. In the context of HPV-mediated cervical cancer, PROTACs can be designed to specifically degrade the E6 and E7 oncoproteins, thereby restoring normal cell cycle control and promoting apoptosis of cancer cells.

Combining exosomes with PROTAC technology offers a synergistic approach to treating HPV-mediated cervical cancer. Exosomes can be engineered to carry PROTACs directly to the cancer cells, ensuring targeted delivery and minimising off-target effects. The encapsulation of PROTACs within exosomes provides protection from enzymatic degradation and enhances the bioavailability of the therapeutic agent. Methods such as electroporation or liposome fusion can be employed to load PROTAC molecules into exosomes effectively. Additionally, surface modification of exosomes with ligands or antibodies specific to HPV-infected or cancerous cells can further enhance targeting precision. This targeted approach not only improves therapeutic efficacy but also reduces systemic toxicity, offering a significant advantage over conventional therapies.

Exosome-based therapy and PROTACs represent a cutting-edge, targeted therapeutic strategy with the potential to transform the treatment landscape for HPV-mediated cervical cancer (Table 1, Figure 1). The natural properties of exosomes, such as their biocompatibility, stability and ability to be engineered for targeted delivery, make them ideal carriers for PROTACs.⁴ The protein-degrading mechanism of PROTACs, coupled with the targeted delivery capabilities of exosomes, offers a promising approach to effectively eliminate HPV oncoproteins and combat cervical cancer. Ongoing research and clinical trials will be crucial in overcoming technical challenges, optimising delivery methods and ensuring the safety and efficacy of these innovative therapies, ultimately paving the way for their successful integration into clinical practice.

Conceptualisation, original draft writing and illustrations: Nobendu Mukerjee and Swastika Maitra. Review and editing: Arabinda Ghosh

The authors declare no potential conflicts of interest.

None.