pH-responsive coacervate with adrenergic nerve blockade function inhibits triple-negative breast cancer metastasis by blocking nerve-tumor-immune loop

Chronic stress, a common comorbidity of breast cancer, is shown to promote tumor progression by affecting tumor microenvironment. Metastasis is the leading cause of death in triple-negative breast cancer (TNBC), and clarifying the specific role of chronic stress on TNBC metastasis will facilitate the development of new targets and improve its prognosis. In this study, a reciprocal nerve-tumor-immune loop is firstly depicted to promote TNBC metastasis under chronic stress and can be interrupted by propranolol (Pro), which shows rapid clinical translation potential due to "new uses for old drugs". However, low bioavailability and insufficient efficacy of Pro when applied systemically may hinder its clinical translation in cancer patients. Based on this, an injectable and pH-responsive Pro-loaded coacervate (Pro@Coa) is further developed, which can accumulate and sustainably release Pro within the tumor. For the first time, the study demonstrates that Pro@Coa not only inhibits TNBC metastasis by interrupting the reciprocal loop but also suppresses distant tumor growth by inducing systemic immunity. Compared to traditional free Pro administration, Pro@Coa improves treatment efficiency and has no side effects on normal tissues. Overall, this work delineates a nerve-tumor-immune loop that promotes TNBC metastasis under chronic stress and provides a reference for applying Pro@Coa for safer and more effective treatment of TNBC metastasis, which is more promising for clinical translation.