Integration of Tumor Elimination And Tissue Regeneration via Selective Manipulation of Physiological Microenvironments Based on Intelligent Nanocomposite Hydrogel for Postoperative Treatment of Malignant Melanoma

Abstract Tumor residue and tissue damage normally occurred after surgical treatment of malignant melanoma, and the effective postoperative therapy is still a challenge because the treatment requests simultaneous but opposite manipulation of tumor cells and healthy cells. Herein, MBGP‐Gel, a thermosensitive and biodegradable hydrogel incorporating S‐nitrosoglutathione (GSNO) loaded and N‐aminoethyl‐N’‐benzoyl thiourea (BTU) modified MSNs (MBGP NPs), was designed to utilize the significant difference of copper content between tumor cells and healthy cells to regulate various physiological microenvironments for integrative therapy of tumor elimination, metastasis inhibition and tissue regeneration. The MBGP‐Gel underwent sol‐gel transformation at body temperature after injection, and continuously released MBGP nanoparticles. In tumor cells, these nanoparticles would chelate the excess copper to inhibit the tumor migration. Meanwhile, copper was reduced to cuprous, which further catalyzed the abundant H₂O₂ and GSNO to produce oxygen species (ROS) and nitric oxide (NO), respectively. The ROS and the reaction product of ROS and NO (ONOO) would significantly damage the tumor tissue. In contrast, MBGP nanoparticles entered healthy cells only generate appropriate amount of NO to accelerate tissue healing. Both in vitro and in vivo results showed that the nanocomposite hydrogel could inhibit the growth and metastasis of malignant melanoma and promote the skin regeneration, which offered an promising strategy for postoperative treatment of various tumors.