A platinum@polymer-catechol nanobraker enables radio-immunotherapy for crippling melanoma tumorigenesis, angiogenesis, and radioresistance

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.