Daily subcutaneous injections of recombinant interleukin-10 (IL-10) demonstrated encouraging but preliminary efficacy in certain tumour types during early phase clinical trials. However, these antitumour effects were not consistently replicated in larger trials, probably due to insufficient intratumoural recombinant IL-10 accumulation, which ultimately restricted clinical benefit. Here we show that intravenous injections of IL-10 messenger RNA (mRNA) nanoparticles (IL-10-mRNA@NPs) induce potent immune surveillance across diverse preclinical tumour models and mitigate systemic toxicities. In particular, IL-10-mRNA@NPs sustain in situ IL-10 production within tumours, promoting substantial infiltration and proliferation of cytotoxic T cells, activation and maturation of dendritic cells, and an augmented expression of major histocompatibility complex class I molecules in immunosuppressive orthotopic early stage hepatocellular carcinoma tumours. Moreover, in mice with orthotopic middle-to-late-stage hepatocellular carcinoma tumours, combining IL-10-mRNA@NPs with immune checkpoint blockades results in 43% of mice showing complete tumour eradication and a sixfold increase in median survival compared with mice treated with immune checkpoint blockades alone. Furthermore, this combination induces long-lasting antitumour immune memory, conferring 100% protection against tumour rechallenges. The intravenous IL-10-mRNA@NPs strategy may have potential to overcome the challenges associated with recombinant IL-10 in clinical trials across a broad spectrum of immunosuppressive tumours.