Biomolecular condensates, which arise from liquid–liquid phase separation within cells, may provide a means of enriching and prolonging the retention of small-molecule drugs within cells. Here we report a method for the controlled in situ formation of biomolecular condensates as reservoirs for the enrichment and retention of chemotherapeutics in cancer cells, and show that the approach can be leveraged to enhance antitumour efficacies in mice with drug-resistant tumours. The method involves histones as positively charged proteins and doxorubicin-intercalated DNA strands bioorthogonally linked via a click-to-release reaction between trans-cyclooctene and tetrazine groups. The reaction temporarily impaired the phase separation of histones in vitro, favoured the initiation of liquid–liquid phase separation within cells and led to the formation of biomolecular condensates that were sufficiently large to be retained within tumour cells. The controlled formation of biomolecular condensates as drug reservoirs within cells may offer new options for boosting the efficacies of cancer therapies.

生物分子缩合物由细胞内液-液相分离产生，可能提供一种富集和延长小分子药物在细胞内保留的方法。在这里，我们报道了一种控制生物分子凝聚物原位形成的方法，作为癌细胞中化疗药物富集和保留的储存库，并表明该方法可用于增强耐药性肿瘤小鼠的抗肿瘤疗效。该方法涉及组蛋白作为带正电荷的蛋白质和阿霉素嵌入的 DNA 链，这些 DNA 链通过反式环辛烯和四嗪基团之间的点击释放反应进行生物正交连接。该反应暂时损害了组蛋白在体外的相分离，有利于细胞内液-液相分离的开始，并导致形成足够大的生物分子缩合物，这些缩合物足以保留在肿瘤细胞内。生物分子凝聚物作为细胞内药物库的受控形成可能为提高癌症治疗的有效性提供新的选择。