Proteins are typically subject to poor stability, short half-life, and poor cell and tissue permeability, which restrict their wide applications as drugs for disease treatment. Current protein modification techniques mostly focus on improving the stability and half-life of proteins, but hardly solve their poor cell and tissue permeability. To address this issue, the study innovatively designs thermo-pH-sensitive elastin-like polypeptides to modify proteins, named ELP(HX) in which histidine (H) and any amino acid except proline (X) are guest amino acids in the polypeptides and n is the total number of the guest amino acids. H in ELP(HX) can be protonated under acidic conditions. To prove the concept, an important protein drug of L-asparaginase (ASP) is genetically fused to ELP(HV) to generate ASP-ELP(HV). Compared with ASP and PEGylated ASP, ASP-ELP(HV) exhibits not only elevated stability and extended half-life but also enhanced tumor cell and tissue penetration, resulting in improved antitumor efficacy. These findings demonstrate that ELP(HX) fusion is a novel and general protein modification method to overcome the intrinsic limitations of proteins as therapeutics, rendering it feasible to design intelligent protein therapeutics, especially for efficient tumor therapy.