Intracellular delivery of proteins remains challenging. Here, we present a simple and general platform for the efficient loading and delivery of proteins using a methoxy-poly(ethylene glycol)-block-poly(L-phosphotyrosine) (mPEG-b-PpY)-templated calcium phosphate (CaP) hybrid nanoparticle. By doping hybrid CaP nanoparticles with Zn²⁺ (CaP-Zn), recombinant proteins bearing a histidine tag can be conveniently loaded by harnessing the His-Zn coordination bond. The resulting protein@CaP-Zn nanoparticles display low toxicity and are tunable, uniform in size, stable under physiological conditions, and degradable in acidic milieu for responsive release. Proteins loaded onto the CaP-Zn nanoparticle can be protected from proteolytic degradation and effectively delivered to intracellular spaces. This work may open up opportunities for protein activity preservation and facilitate the intracellular delivery of recombinant protein therapeutics.

蛋白质的细胞内递送仍然具有挑战性。这里，我们提出了高效装载和使用甲氧基聚（乙二醇）的蛋白质的递送的简单和通用的平台-嵌段-聚（L-磷酸酪氨酸）（的mPEG- b -PpY）-templated磷酸钙（CAP）的混合纳米粒子。通过用 Zn ²⁺掺杂混合 CaP 纳米粒子(CaP-Zn)，带有组氨酸标签的重组蛋白可以通过利用 His-Zn 配位键方便地加载。由此产生的蛋白质@CaP-Zn 纳米颗粒具有低毒性、可调节、尺寸均匀、在生理条件下稳定、在酸性环境中可降解以响应释放的特点。加载到 CaP-Zn 纳米颗粒上的蛋白质可以防止蛋白水解降解并有效地传递到细胞内空间。这项工作可能为蛋白质活性的保存开辟了机会，并促进了重组蛋白质疗法的细胞内递送。