Ascorbate/methionine-based CH₄ delivery nanomedicine for tumor-targeted therapy

Methane (CH₄) is identified to be an emerging anti-inflammation and anti-cancer molecule with high bio-safety, but the targeted delivery of CH₄ is a thorny challenge. Herein, we propose a CH₄ delivery strategy based on an intratumoral H₂O₂-triggered cascade reaction of ascorbic acid (AA)/methionine (Met), and have constructed a new nanomedicine (AMN) for tumor-targeted CH₄ therapy. Encouragingly, AMN realizes the effective tumor-targeted delivery and intratumoral H₂O₂-responsive release of CH₄, and exhibits significant anti-cancer effects and high bio-safety. Mechanistically, we have discovered that intratumoral released CH₄ can not only induce the apoptosis of 4T1 tumor cells by inhibiting their mitochondrial metabolism, but also activate tumor immunotherapy by reprogramming tumor-associated macrophages (TAMs) phenotype (M2 to M1). The combination of the above anti-cancer pathways by virtue of tumor-targeted CH₄ delivery makes contribution to outstanding anti-cancer efficacy of AMN. The proposed CH₄ delivery strategy opens a new window for safe and effective tumor therapy.