In Vivo-Assembled Artificial Base-Albumin Platform for Tumor-Targeted General Drug Delivery

Chemotherapy can lead to severe side effects owing to drug accumulation in normal tissues and organs. As a countermeasure, targeted drug delivery strategies have been developed, including albumin-PTX (nab-PTX) approved by the FDA. Previously, we reported an artificial nucleobase containing fluorine, the F-base, which can interact with albumin for oligonucleotide tumor-targeted delivery. Here, we systematically assessed the potential of an in vivo-assembled platform for the delivery of tumor-targeted chemotherapeutic drugs, whereby molecular precursors self-assembled into nanostructures at the tumor site. Chemotherapeutic drugs, including 5-fluorouracil, gemcitabine, and monomethyl auristatin E, were first incorporated into oligonucleotides, a targeting molecule, to form a drug-loaded DNA sequence. Subsequent introduction of an F-base at both ends of the targeting molecule resulted in enhanced therapeutic potential. The assembly of F-drugs combined with albumin was characterized and verified, and the cytotoxicity, biodistribution, pharmacokinetics, therapeutic efficiency, and biosafety were analyzed. The results showed that the F-base modification improved drug stability, penetrability, and cytotoxicity in vitro. Longer circulation times, higher tumor enrichment, and improved antitumor effects were observed in CDX, PDX, and murine orthotopic tumor model. Together, the findings introduce an F-based delivery system that boosts both the solubility and tumor penetration of chemotherapeutics, offering a promising approach for targeted cancer therapy.