Abstract

Chronic stress significantly impacts cancer progression by activating the sympathetic nervous system, leading to increased tumor growth, metastasis, and resistance to chemotherapy. To address these challenges, we develop biomimetic hybrid nanovesicles (Pro@hNVs) by fusing M1 macrophage-derived vesicles with pH-sensitive liposomes (hNVs) to encapsulate the β-adrenergic receptor (ADRB) blocker propranolol (Pro). Leveraging the tumor-targeting properties of M1 macrophage-derived vesicles and their matrix metalloproteinase-mediated degradation of tumor extracellular matrix, Pro@hNVs effectively accumulate and deeply penetrate tumor tissues, followed by the release of Pro in response to the acidic tumor microenvironment. Pro subsequently inhibits the sympathetic nerve-cancer cell crosstalk by blocking ADRB2 signaling. Meanwhile, Pro@hNVs effectively reprogram adrenergic signal-induced M2-like tumor-associated macrophages (TAMs) into the M1 phenotype through the released Pro and hNVs, thereby amplifying TNF-mediated neurotoxicity and effectively disrupting sympathetic nerve-macrophage crosstalk. This dual-action mechanism of Pro@hNVs significantly inhibits the sympathetic nerve function promoted by gemcitabine, resulting in the improved chemotherapy efficacy and enhanced antitumor immune response under chronic stress. These findings highlight the potential of Pro@hNVs as a promising strategy to enhance chemotherapy outcomes in cancer patients experiencing chronic stress, offering a viable therapeutic avenue for overcoming treatment resistance.