Malignant melanoma cell-intrinsic PD-1:PD-L1 interaction thrusts
tumorigenesis, angiogenesis, and radioresistance via mTOR hyperactivation to aggravate circumjacent aggression. Interdicting
melanoma intrinsic growth signals, including the blockade of PD-L1 and mTOR signaling concurrently, cooperative with
radiotherapy may provide a vigorous repertoire to alleviate the
tumor encumbrance. Thence, we design a three-pronged
platinum@
polymer-
catechol nanobraker to deliver mTOR inhibitor TAK228 and anti-PD-L1 antibody (aPD-L1) for impeding the melanoma-PD-1-driven aggression and maximizing the
melanoma eradication. The aPD-L1 collaborated with TAK228 restrains
melanoma cell-intrinsic PD-1: PD-L1 tumorigenic interaction via blocking melanoma-PD-L1
ligand and the melanoma-PD-1 receptor-driven mTOR signaling; corresponding downregulation of mTOR downstream protumorigenic cellular MYC and proangiogenic
hypoxia-inducible factor 1-alpha is conducive to preventing
tumorigenesis and angiogenesis, respectively. Further, high-Z
metal platinum sensitizing TAK228-enhanced
radiotherapy confers the nanobraker on remarkable tumoricidal efficacy. Hereto, the customized three-pronged nanobrakers efficiently suppress
melanoma tumorigenesis and angiogenesis concomitant with the amplification of radiotherapeutic efficacy. Such an ingenious tactic may provide substantial benefits to clinical
melanoma patients.