Development of a novel Cu-Mn hydroxide layered nanosheet-loaded drug modulating the tumour microenvironment and...

The tumor microenvironment (TME) impedes the effectiveness of therapeutic strategies such as chemodynamic therapy (CDT). This study presents a novel nanoscale drug delivery system designed for the precise release of the chemotherapeutic agent doxorubicin (DOX), aiming to overcome treatment limitations, reduce systemic toxicity, and enhance antitumor efficacy. Mn(III) serves as an immunomodulatory agent, while Cu(II) regulates the levels of glutathione (GSH). Layered double hydroxides (LDHs) were synthesized and efficiently loaded with DOX, followed by surface modification with hyaluronic acid (HA). The HA-coated LDH/DOX nanocarriers showed effective internalization by tumor cells and provided a pH-responsive release of DOX. In vitro, the LDH/HA/DOX complex exhibited strong catalytic activity in the Fenton reaction. In vivo studies using an H22 hepatocarcinoma model confirmed its potent antitumor activity and excellent biocompatibility. Immunohistochemical analyses revealed that treatment with LDH/HA/DOX significantly increased infiltration of M1-polarized tumor-associated macrophages (TAMs), CD4 + T cells and CD8 + T cells, while decreasing M2-polarized TAMs. This change in immune cell profile was associated with notable tumor growth inhibition.