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Platinum(II)-based drugs (PtII), which hinder DNA replication, are the most widely used chemotherapeutics. However, current PtII drugs often miss their DNA targets, leading to severe side effects and drug resistance. To overcome this challenge, we developed a oxaliplatin-based platinum(IV) (PtIV) prodrug amphiphile (C 16 -OPtIV-R 8 K), integrating a long-chain hydrophobic lipid and a nucleus-targeting hydrophilic peptide (R 8 K). This design allows the prodrug to self-assemble into highly uniform lipid nanoparticles (NTPtIV) for enhanced targeting chemotherapy and immunotherapy. Subsequently, NTPtIV's bioactivity and effects were examined at diverse levels, encompassing cancer cells, 3D tumor spheres, and in vivo. Our in vitro studies show a 74% cancer cell nucleus localization of platinum drugs-3.6 times higher than that of oxaliplatin, achieving more than a ten-fold increase in eliminating drug-resistant cancer cells. In vivo , NTPtIV shows efficient tumor accumulation, leading to suppressed tumor growth of murine breast cancer. Moreover, NTPtIV recruited more CD4+ and CD8+ T cells and reduced CD4+ Foxp3+ Tregs to synergistically enhance targeted chemotherapy and immunotherapy. Overall, this strategy presents a promising advancement in nucleus-targeted cancer therapy, synergistically boosting the efficacy of chemotherapy and immunotherapy. Nucleus-targeted Pt lipid nanoparticles (NTPtIV) assembled by amphipathic PtIV prodrug (C 16 -OPtIV-R 8 K) with 74% efficiency to enable accumulation of Pt drugs in the cancerous nucleus for enhanced targeted chemotherapy and immunotherapy. [Display omitted] • A novel PtIV prodrug amphiphile (C 16 -OPtIV-R 8 K) for nucleus-targeting. • Nano-assembly nucleus-targeted PtIV lipid nanoparticles NTPtIV with 74% efficiency was obtained. • NTPtIV improves the endocytosis and nuclear targeting efficiency of Pt via lipidation and R 8 K. • NTPtIV induces cancer cell death and reverses Pt-based drug resistance for targeted chemotherapy and enhanced immunotherapy. [ABSTRACT FROM AUTHOR]

The development of PtIV prodrugs which are selectively reduced within cancerous cells into their PtII therapeutically active species has received increasing attention within the last decade. Despite recent research progress, the majority of investigated compounds are excited using ultraviolet or blue light. As the light penetration depth is low at these wavelengths, the treatment of deep‐seated or large tumors is limited. To overcome this limitation, herein, the example of PtIV‐functionalized nanoparticles that could be excited within the NIR region at 808 nm is reported. The polymer backbone which can self‐assemble into nanoparticles was functionalized with PtIV complexes for chemotherapy, photosensitizers for photodynamic immunotherapy, and nucleus/cancer‐targeting peptides. Upon irradiation, the PtIV center is reduced to PtII and the axially coordinated ligands are released, presenting a multimodal treatment. While selectively accumulating in tumorous tissue, the nanoparticles demonstrated the ability to eradicate a triple‐negative breast cancer tumor inside a mouse model. [ABSTRACT FROM AUTHOR]

Ovarian cancer has the highest death rate in gynecologic tumors and the main therapy for patients with advanced is chemotherapy based on cisplatin. Additionally, hyperthermic intraperitoneal has been used in clinic to obtain better efficacy for patients. Hence, combined photothermal therapy with platinum drugs in a new delivery system might bring new hope for ovarian cancer. A reduction sensitive polymer encapsulating a Pt (IV) prodrug and a near infrared II (NIR II) photothermal agent IR1048 to form nanoparticles were reported to enhance the efficacy of ovarian cancer treatment. At the same time, endoplasmic reticulum stress indicates an imbalance in proteostasis which probably caused by extrinsic stress such as chemotherapy and the temperature changed. The efficacy of nanoparticles containing Pt (IV) and IR1048 under NIR II light might be caused via increased DNA damage and endoplasmic reticulum (ER) stress. [ABSTRACT FROM AUTHOR]