Radiolabeled Coordination Polymer-Loaded Microneedles for Synergistic Melanoma Brachytherapy–Immunotherapy via STING Activation and Pyroptosis

Abstract

Melanoma remains a highly aggressive malignancy with limited response to current immunotherapies due to its immunosuppressive tumor microenvironment. To overcome this limitation, we developed a radiolabeled coordination polymer, ¹⁷⁷Lu-GAMP, through the self-assembly of ¹⁷⁷Lu³⁺ with adenosine monophosphate (AMP) and guanosine monophosphate, exhibiting coordination-feature resemblance to the endogenous STING agonist cGAMP, thereby enabling activation of the STING pathway. We further incorporated ¹⁷⁷Lu-GAMP into a dissolvable microneedle patch (¹⁷⁷Lu-GAMP@MN) for localized, minimally invasive delivery to melanoma lesions. Our results demonstrate that ¹⁷⁷Lu-GAMP@MN effectively penetrated the skin and retained at the tumor site, leading to robust STING activation and Gasdermin E-mediated pyroptosis. This, in turn, promoted dendritic cell maturation and enhanced T cell infiltration. In vivo, ¹⁷⁷Lu-GAMP@MN significantly suppressed subcutaneous melanoma growth, prolonged survival, and elicited strong antitumor immune responses. When combined with anti-PD-L1 monoclonal antibodies, the treatment achieved synergistic tumor regression, improved effector T cell function, and induced durable immunological memory, demonstrating significant inhibition of both primary and distant tumors in murine models. Collectively, this work presents a transdermal brachytherapeutic-immunomodulatory strategy for melanoma treatment, offering promising potential for enhanced antitumor immunotherapy.

Keywords

melanoma / STING pathway / pyroptosis / radiolabeled coordination polymers / microneedles

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