Lipid nanoparticle co-delivery of mRNA and a small molecule drug for oral cancer chemoimmunotherapy

Nov 19, 2025bioRxiv : the preprint server for biology

Using tiny fat-based particles to deliver mRNA and a small drug together for combined chemotherapy and immune therapy in oral cancer

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Abstract

The overall incidence rate of oral squamous cell carcinoma (OSCC) is projected to increase by 30% in the next ten years.

Oral squamous cell carcinoma (OSCC) accounts for 90% of head and neck cancers.
The current 5-year survival rate for OSCC is 50%.
OSCC progression is associated with the inactivation and mutation of tumor suppressor genes.
The tumor immune microenvironment in OSCC is characterized as 'cold', limiting effective immune responses.
A lipid nanoparticle co-encapsulating p53 mRNA and ciclopirox (CPX) may enhance therapeutic effects by activating caspases.
This combined therapy could potentially reshape the immune environment by repolarizing tumor-associated macrophages to a more active state.

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Oral squamous cell carcinoma (OSCC) represents 90% of all head and neck cancers. Despite decades of research, the 5-year survival rate is 50%, and strikingly, the overall incidence rate is projected to increase by 30% in the next ten years, which will result in a sharp increase in mortality. Two fundamental aspects of OSCC are that it progresses via the inactivation and mutation of tumor suppressor (TS) genes and has a "cold" tumor immune microenvironment (TIME). A major barrier in the treatment of OSCC is the lack of novel therapies clinicians have at their disposal that are designed to disrupt tumor progression by reshaping the cold tumors into inflammatory "hot" tumors. To overcome these obstacles, we employed a lipid nanoparticle (LNP) that co-encapsulates p53 mRNA and the small molecule ciclopirox (CPX). We demonstrate that both drugs have innate chemotherapeutic properties by facilitating caspase activation. Moreover, these therapies can create a less immunosuppressive TIME in part by repolarizing tumor-associated macrophages (TAMs) to M1-like phenotypes. When formulated together, our platform provides an all-in-one approach for OSCC, effective in both p53-therapy-susceptible and p53-therapy-resistant models. Additionally, this work provides a template for a delivery platform capable of tackling multiple mechanisms of OSCC progression and survival.