Self-assembled HO-1i-Pt(IV) nanomedicine targeting p38/MAPK and MDR pathways for cancer chemo-immunotherapy.

Platinum(II)-based antitumor drugs are widely used in clinics but limited by severe side effects and resistance. Multi-target Platinum(IV) complexes are emerging as ideal alternatives. Heme oxygenase-1 (HO-1) works as a rate-limiting step in heme degradation and is overexpressed in malignant tumors. Herein, HO-1i-based Platinum(IV) prodrugs are prepared and candidate complex 15 is further developed into self-assembled nanoparticles (15-NPs). 15 and 15-NPs significantly increase cytotoxicity, particularly in HepG2 (74.77- and 96.14-fold increases) and A549cisR (38.6- and 47.24-fold increases), while reducing toxicity towards normal cells compared to cisplatin. In vitro experiments show 15 and 15-NPs activated multiple pathways, including p38/MAPK- and MDR-related proteins, achieving multi-target synergistic chemosensitization and anti-resistance, further verified by RNA-sequencing analysis. In vivo tests demonstrate that 15 and 15-NPs efficiently inhibit tumor growth and systemic toxicity, especially 15-NPs with optimal tumor-inhibition rate and survival (80% and 100%), superior to cisplatin (40% and 50%), attributing to its extra endocytosis, EPR effect, and precisely tumor-targeted release besides the advantage of a free HO-1i-Pt(IV) prodrug. Additionally, 15 and 15-NPs distinctly regulate T-cell and macrophage functions, thereby exhibiting a chemoimmuno-combined action. This study highlights that multi-functional Platinum(IV) prodrug target-delivered to tumors via carrier-free nanoparticles may represent an effective modality for improving cancer therapy.