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Immunotherapy with immune checkpoint blockade (ICB) has shown limited benefits in hepatocellular carcinoma (HCC) and other cancers, mediated in part by the immunosuppressive tumor microenvironment (TME). As p53 loss of function may play a role in immunosuppression, we herein examine the effects of restoring p53 expression on the immune TME and ICB efficacy. We develop and optimize a CXCR4-targeted mRNA nanoparticle platform to effectively induce p53 expression in HCC models. Using p53 -null orthotopic and ectopic models of murine HCC, we find that combining CXCR4-targeted p53 mRNA nanoparticles with anti-PD-1 therapy effectively induces global reprogramming of cellular and molecular components of the immune TME. This effect results in improved anti-tumor effects compared to anti-PD-1 therapy or therapeutic p53 expression alone. Thus, our findings demonstrate the reversal of immunosuppression in HCC by a p53 mRNA nanomedicine when combined with ICB and support the implementation of this strategy for cancer treatment. The p53 tumor suppressor gene is frequently mutated in liver cancer. Here the authors show that restoration of p53 expression with a mRNA nanoparticle platform elicits anti-tumor immune responses and promotes response to immune checkpoint blockade in preclinical models of p53-null hepatocellular carcinoma.

Ribonucleic acid (RNA) drugs have shown promising therapeutic effects for various diseases in clinical and preclinical studies, owing to their capability to regulate the expression of genes of interest or control protein synthesis. Different strategies, such as chemical modification, ligand conjugation, and nanotechnology, have contributed to the successful clinical translation of RNA medicine, including small interfering RNA (siRNA) for gene silencing and messenger RNA (mRNA) for vaccine development. Among these, nanotechnology can protect RNAs from enzymatic degradation, increase cellular uptake and cytosolic transportation, prolong systemic circulation, and improve tissue/cell targeting. Here, a focused overview of stimuli‐responsive nanotechnologies for RNA delivery, which have shown unique benefits in promoting RNA bioactivity and cell/organ selectivity, is provided. Many tissue/cell‐specific microenvironmental features, such as pH, enzyme, hypoxia, and redox, are utilized in designing internal stimuli‐responsive RNA nanoparticles (NPs). In addition, external stimuli, such as light, magnetic field, and ultrasound, have also been used for controlling RNA release and transportation. This review summarizes a wide range of stimuli‐responsive NP systems for RNA delivery, which may facilitate the development of next‐generation RNA medicines. Ribonucleic acid (RNA) therapeutics have demonstrated great potential for treating various diseases. Nanoparticle delivery technologies can protect RNAs from degradation, increase cellular uptake and cytosolic transportation, prolong systemic circulation, and improve tissue/cell targeting. The review summarizes a wide range of stimuli‐responsive nanoparticle systems for RNA delivery, highlighting their unique features and offering insights into the development of next‐generation RNA nanomedicines.

Spinal cord injury (SCI) is a severe neurological disorder for which meaningful functional recovery remains difficult to achieve. RNA therapeutics offer a promising strategy for neural repair, but their application is limited by the need for efficient and sustained delivery to injured spinal tissue. In this study, aminophosphonate-derived lipid nanoparticles were screened to identify an effective RNA delivery platform for SCI. Because linear mRNA expression in vivo was not sufficiently durable, circular RNA was adopted as a more stable alternative, and a simplified high-temperature two-step synthesis method was used to improve circular RNA production efficiency. Using this optimized platform, circular Sox2 and Ascl1 were delivered locally to the lesion site, followed by systemic delivery of circular GDNF. This treatment improved bladder function, locomotor recovery, and histological evidence of neuronal regeneration in SCI mice, supporting circular RNA-loaded lipid nanoparticles as a promising therapeutic strategy for spinal cord repair.

Sensory neurons within the dorsal root ganglion (DRG) are the primary trigger of pain, relaying activity about noxious stimuli from the periphery to the central nervous system; however, targeting DRG neurons for pain management has remained a clinical challenge. Here, we demonstrate the use of lipid nanoparticles (LNPs) for effective intrathecal delivery of small interfering RNA (siRNA) to DRG neurons, achieving potent silencing of the transient receptor potential vanilloid 1 (TRPV1) ion channel that is predominantly expressed in nociceptor sensory neurons. This leads to a reversible interruption of heat-, capsaicin-, and inflammation-induced nociceptive conduction, as observed by behavioral outputs. Our work provides a proof-of-concept for intrathecal siRNA therapy as a novel and selective analgesic modality.