Recent advances in lipid nanoparticles for cancer vaccine delivery: Challenges and future perspectives.

Cancer remains a major global health burden, with 19.3 million new cases and 10.3 million deaths reported in 2020. Conventional modalities such as surgery, radiotherapy, and chemotherapy often fail to prevent metastasis or recurrence. Cancer vaccination, which mobilizes durable, tumor-specific immunity, has gained traction, and LNPs have become pivotal to this approach. Originally optimized for siRNA, LNPs' core-shell architecture protects nucleic acids, enhances cellular uptake, and enables efficient cytosolic delivery. Their clinical validation in infectious-disease messenger RNA (mRNA) vaccines has catalyzed rapid progress toward oncology applications. Preclinical and early-phase trials have indicated that mRNA-LNPs encoding tumor-associated antigens or patient-specific neoantigens can expand cytotoxic T cells and elicit preliminary antitumor activity. Key barriers remain. Manufacturing cost and batch consistency challenge scale-up. Physicochemical instability necessitates cold-chain logistics and complicates global deployment. Reactogenicity and anti-PEG antibodies increase safety and dosing concerns. Within tumors, immunosuppressive microenvironments, heterogeneous antigen expression, and suboptimal lymphoid targeting limit the efficacy of vaccines. This review describes the advances in LNP design (ionizable and biodegradable lipids, PEG alternatives, ligand-mediated targeting), formulation strategies (thermostable and lyophilized systems), and delivery routes (intranodal and intratumoral) to overcome these bottlenecks. It also highlights synergistic combinations with checkpoint blockade, radiotherapy, and innate agonists, and examines emerging pipelines leveraging AI-guided neoantigen discovery and quality control. By integrating material engineering, immunology, and translational evidence, we identified failure points and proposed a roadmap for next-generation LNP-based cancer vaccines. The goal is to accelerate progress from bench to clinic, while improving manufacturability, access, and durable patient benefits.