Lipid nanoparticles (LNPs) have emerged as promising carriers for the systemic delivery of messenger RNA (mRNA). However, it remains challenging that mRNA should be stably encapsulated during blood circulation but quickly released in the cytoplasm for translation. To address these issues, we report a combinatorial library of esterase-responsive quaternized lipidoids screened for LNP capable of efficient mRNA delivery and potent immune activation in vivo. The optimized formulation, AMB-AOC18 LNPs, can encapsulate mRNA stably during long-term storage, bypass the lysosomal trap after internalization, and completely release mRNA into the cytoplasm in response to the elevated esterase levels, leading to enhanced transfection efficiency. Interestingly, intravenously administered AMB-AOC18 LNPs can navigate to the spleen and selectively transfect antigen-presenting cells (APCs), rather than other organs. As a result, AMB-AOC18 LNPs containing ovalbumin (OVA)-encoded mRNA provoke robust OVA-specific T lymphocyte responses, remarkably inhibiting tumor growth and lung metastasis and extending mice survival in the melanoma tumor model. This study highlights the potential application of these esterase-responsive lipidoids for mRNA delivery and promises a feasible approach toward tumor therapy and vaccination.

Organ-selective mRNA delivery of esterase-responsive lipid nanoparticles for tumor immunotherapy

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