Biomimetic Sealing of Cisplatin by Cancer Cell Membranes to Achieve Nucleophile Resistance and Tumor Targeting for Improved Cancer Therapy.

Platinum-based anticancer drugs (PBCs), particularly cisplatin, play a key role in over 70% of cancer treatment protocols. PBCs suffer from their strong affinity with numerous nucleophiles present in the body, leading to significant systematic toxicity and rapid drug inactivation. The cell membrane's selective and energy-dependent transport properties, inherent to its unique biological structure, offer a strategic opportunity for employing cell membranes (CMs) in the development of PBC delivery systems that repel nucleophiles. To prove this idea, we harness cancer CMs to develop a dual-package approach for sealing cisplatin in a nanoformulation that is both nucleophile-resistant and tumor-targeted without the need for synthetic materials. The dual-package process begins by conjugating cisplatin to cancer CMs, creating positively charged nanoparticles. These isolated nanoparticles are then recomplexed with cancer CMs. Our strategy, which tightly seals cisplatin within the cancer CMs, ensures that cisplatin is safely sequestered from reactive molecules in the body while simultaneously guiding it specifically to homologous tumors. The resulting nanoformulation demonstrates immune evasion and a prolonged circulation time due to the native-like identity conferred by cancer CMs. The biomimetic sealing of cisplatin within CMs prevented the transmembrane attack of nucleophiles, including not only macromolecular proteins but also small-molecule compounds such as glutathione, thereby ensuring a high level of cytotoxicity when challenged by these nucleophiles. It also displays precise targeting at homologous tumors, ensures sustained drug release, and achieves significant tumor suppression. These features together adumbrate the nanoformulation's potential as a revolutionary tool in cisplatin cancer therapy. Given the prevalence of metal ion-based drugs and their common susceptibility to nucleophile-associated issues, the strategy presented in this study may offer a widely applicable solution to developing nucleophile-resistant metal-ion-based medications.