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.

由细胞内液-液相分离产生的生物分子凝聚物可以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，我们报告了一种控制原位形成生物分子凝聚物的方法，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肿瘤小鼠的抗肿瘤功效。该方法涉及作为带正电荷的蛋白质的组蛋白和通过反式环辛烯和四嗪基团之间的点击释放反应生物正交连接的阿霉素插入的DNA链。该反应暂时损害了体外组蛋白的相分离，有利于细胞内液-液相分离的启动，并导致形成足够大的生物分子凝聚物以保留在肿瘤细胞内。作为细胞内药物储存库的生物分子凝聚物的受控形成可能为提高癌症治疗的功效提供新的选择。