Zinc-enriched nanosystem for dual glycolysis regulation and photothermal therapy to synergistically inhibit primary melanoma and lung metastasis

Despite significant progress in melanoma treatment, low therapeutic efficacy frequently occurs in advanced-stage patients due to distant organ metastasis. We herein propose a zinc-enriched nanosystem (Lornidamine@HMPB-Zn) with high photothermal conversion efficacy for dual glycolysis regulation and photothermal therapy. Lornidamine@HMPB-Zn comprises zinc-bonded hollow mesoporous Prussian blue (HMPB-Zn) nanoparticles as a photothermal converter, dissociated zinc ions, and the loaded lonidamine as a glycolysis regulator. Upon near infrared (NIR) laser irradiation, the heat energy generated by HMPB-Zn not only did induce cytotoxicity but also accelerated the dissociation of zinc ions and the release of LND, respectively inhibiting lactate dehydrogenase (LDHA) and hexokinase II (HK2) to down-regulate the level of glycolysis. Additionally, the down-regulated expression of Akt, p-Akt, HIF-1 alpha and cell cycle arrest induced by this nanosystem contributed to the potent antitumor efficacy in vitro and in vivo. Notably, the synergistic treatment nanosystem reduced the expression of metastasis-related proteins, inhibiting distant metastasis from subcutaneous melanoma to lung lesion. Thus, the present study provides a novel perspective for tumor metabolism and phototherapy to achieve complete tumor regression.

Automated summary

In this study, a zinc-enriched nanosystem was developed for the treatment of melanoma. The nanosystem demonstrated high photothermal conversion efficacy and was able to regulate glycolysis and provide photothermal therapy. Upon laser irradiation, the nanosystem generated heat energy and released glycolysis regulators, resulting in the inhibition of lactate dehydrogenase and hexokinase II and down-regulation of glycolysis. Additionally, the nanosystem showed potent antitumor efficacy by down-regulating the expression of Akt, p-Akt, HIF-1 alpha, inducing cell cycle arrest, and inhibiting distant metastasis. Overall, this study provides a novel perspective for tumor metabolism and phototherapy to achieve complete tumor regression.