Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer, and the number of new cases is predicted to rise by 30% in the next decade.
Despite decades of cancer research, treating OSCC remains a challenge. The five-year survival rate is approximately 50%, and standard treatments such as ablative surgery and radiation often leave patients with permanent disfigurement or profound, lifelong impairment of essential oral functions such as speaking and swallowing.
Now, using lipid nanoparticles (LNPs), a multidisciplinary team of Penn researchers led by Michael Mitchell of the School of Engineering and Applied Sciences and Anh D. Le of the School of Dental Medicine has developed a platform that delivers a combination of cancer-fighting therapies to treat OSCC. The findings are published in Advanced Materials .
“mRNA lipid nanoparticles are a potentially promising technology to treat oral cancer, since tumors are accessible locally and can also be leveraged to generate a systemic immune response that targets metastatic tumors,” says Mitchell, the Hibbert Professor of Bioengineering and the Lipid Nanoparticle Delivery Systems Group Leader at the Penn Institute for RNA Innovation . “However, tumor cells can be difficult to target and deliver mRNA into, so we designed a novel LNP delivery system for delivery into oral cancer cells.”
The versatility of this platform means that it could benefit far more patients than traditional single-agent therapies, says Le, the Norman Vine Endowed Professor of Oral Rehabilitation, “opening the door to a broader, more effective class of treatments.”
Taking a two-pronged approach
More than 70% of OSCC cases involve mutations in p53, a common tumor suppressor protein; ciclopirox is an FDA-approved antifungal drug with anti-cancer and immunotherapy activity.
Because both of these drugs require a drug delivery carrier, the team encapsulated them in a single LNP formulation.
Together, these two therapies act simultaneously through multiple mechanisms, directly killing cancer cells while reprogramming the immune system to target them instead of protecting them, says first author Marshall Padilla , a former postdoctoral fellow in the Department of Bioengineering and the Center for Innovation & Precision Dentistry (CiPD). “The potential shift is from one-size-fits-all monotherapy toward a single, tunable delivery vehicle that works even when one of its two drugs fails, which matters because oral tumors vary enormously from patient to patient.”
The team found that both p53 and ciclopirox have innate chemotherapeutic properties. In addition, these drugs can create a less immunosuppressive tumor microenvironment.
“In aggressive, p53-therapy-resistant cancer models, this new LNP platform significantly reduces tumor burden and extends survival,” says Le, also the chair of the Department of Oral & Maxillofacial Surgery / Pharmacology .
Advancing the science through continued collaboration
Looking ahead, the team plans to continue to partner to advance this work.
“The mechanism of how ciclopirox and p53 reprogram tumor-associated macrophages isn't fully worked out,” says Padilla. “The paper points to a plausible pathway but flags that it needs to be confirmed.”
Future efforts will include refining the nanoparticle design for greater precision; expanding the therapeutic payloads beyond p53 and ciclopirox; and moving toward different delivery routes. The team also plans to test the platform in more complex preclinical models against the genetic diversity of real patient tumors—the variability of which has historically “sunk” p53 therapies, says Padilla.
“This work opens the door to an entirely new class of customizable nanotherapies for oral cancer,” says Le. “This breakthrough was only possible because Penn’s deeply collaborative culture brings engineers, clinicians, and scientists into the same space—often tackling the same unmet clinical need—creating the kind of cross-disciplinary momentum that enables advances like this.”
Michael Mitchell is the Hibbert Professor of Bioengineering at Penn Engineering and the Lipid Nanoparticle Delivery Systems Group Leader at the Penn Institute for RNA Innovation. He is also a core member of CiPD.
Anh D. Le is the chair and Norman Vine endowed professor of oral rehabilitation for the Department of Oral & Maxillofacial Surgery / Pharmacology at Penn Dental Medicine. She is also a core member of CiPD.
Marshall Padilla was a postdoc in the Mitchell lab and is now an assistant professor in the Department of Materials Science & Engineering and a Sarafan ChEM-H Institute Scholar at Stanford University.
Other authors are Shihong Shi, Qunzhou Zhang of Penn Dental, Ori Z. Chalom, Emily Fitzgerald, Briyanna N. Hymms, Ryann A. Joseph, Jacqueline J. Li, Korey Patwari, Sridatta V. Teerdhala, Hannah M. Yamagata of Penn Engineering, and Mohamad-Gabriel Alameh, Kushol Gupta, Drew Weissman of the Perelman School of Medicine .
M.S.P. acknowledges support from the National Institute of Dental & Craniofacial Research (NIDCR) of the National Institutes of Health (NIH) under Award Number T90DE030854 and the Center for Innovation & Precision Dentistry (CiPD) at the University of Pennsylvania. Q.Z. and A.D.L. acknowledge an NIH/NIDCR grant (R01 DE031023). O.Z.C. acknowledges a National Science Foundation grant (DBI-2400135). M.J.M. acknowledges the US National Science Foundation CAREER award (CBET-2145491) and an American Cancer Society Research Scholar Grant (RSG-22-122-01-ET).
Advanced Materials
Experimental study
Animals
Lipid Nanoparticle Co-Delivery of mRNA and a Small Molecule Drug for Oral Cancer Chemoimmunotherapy
14-Jul-2026
M.S.P. and M.J.M. have a patent related to the structure of the BEND lipids and their biological applications (U.S. Provisional Patent Appl. No. 63/373,793, filed August 29, 2022).