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 radio-resistance via mTOR hyperactivation to aggravate circumjacent aggression. Interdicting melanoma intrinsic growth signals, including the blockade of PD-L1 and mTOR signaling concurrently, cooperative with radio-therapy 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 sub-stantial benefits to clinical melanoma patients.

Automated summary

The interaction between PD-1 and PD-L1 in malignant melanoma cells promotes tumorigenesis, angiogenesis, and radio-resistance through mTOR hyperactivation. Blocking PD-L1 and mTOR signaling concurrently, along with radiotherapy, can alleviate tumor burden. A three-pronged platinum@polymer-catechol nanobraker, delivering mTOR inhibitor TAK228 and anti-PD-L1 antibody, effectively inhibits melanoma-PD-1-driven aggression and enhances melanoma eradication, while also amplifying the efficacy of radiotherapy.