Polymeric and Lipid Nanoparticles forTargeted Chemotherapy in Oral SquamousCell Carcinoma: Advances, Challenges,and Future Prospects

Abstract

Oral squamous cell carcinoma (OSCC) remains a lethal malignancy with a persistently high mortality rate, largely due to
late-stage diagnosis, dose-limiting systemic toxicities of conventional chemotherapy, and the development of multidrug
resistance. This review comprehensively examines the transformative role of nanotechnology, specifically polymeric and
lipid nanoparticles (LNPs), in overcoming these hurdles for targeted chemotherapy. We detail the advances in nanoparticle
(NP) design, including the use of biodegradable polymers like poly(lactic-co-glycolic acid) and chitosan, and versatile
lipid-based systems such as solid LNPs and nanostructured lipid carriers. A key focus is placed on the engineering
of “smart,” multifunctional NPs that respond to specific tumor microenvironment stimuli (e.g., pH, temperature, and
enzymes) for spatiotemporally controlled drug release. Furthermore, we explore active targeting strategies using ligands
(e.g., folic acid, hyaluronic acid) and biomimetic coatings (e.g., macrophage membranes) to enhance tumor specificity
and immune evasion. Despite the promising preclinical success, significant challenges impede clinical translation,
including concerns over nanotoxicity, complex scalability, tumor heterogeneity, and evolving regulatory landscapes. The
future of OSCC nanomedicine lies in the convergence of artificial intelligence for rational NP design, the co-delivery
of chemotherapeutics with resistance-inhibiting agents, and a steadfast push toward personalized, stimuli-responsive
therapies. This review concludes that polymeric and LNPs hold immense potential to redefine the therapeutic paradigm
for OSCC, offering a path to improved efficacy, reduced side effects, and better patient outcomes.