Reducing chemotherapy toxicity without compromising efficacy remains one of the major challenges in oncology. A research team from the Institut de Recerca Sant Pau (IR Sant Pau) has shown in a study published in Materials Today Bio that a more precise design strategy in nanomedicine can maintain—and even improve—the antitumor effect while using much smaller amounts of drug.
“For years it has been assumed that increasing the amount of drug was the way to improve efficacy, but our results do not support that assumption. What is truly decisive is how and where the drug binds to the nanocarrier,” explains Dr. Ugutz Unzueta, researcher in the Oncogenesis and Antitumor Drugs group at IR Sant Pau. “A precise structural design makes it possible to use the drug much more efficiently and reduce the required dose.”
Targeted therapies have transformed cancer treatment by enabling the delivery of highly potent drugs directly to tumor cells. However, even the most advanced strategies, such as antibody–drug conjugates, still present relevant limitations, including suboptimal biodistribution or toxicities that restrict the administrable dose.
“The challenge is no longer only to direct the drug to the tumor, but to do so with the greatest possible precision so that every molecule counts,” notes Dr. Unzueta. “If we do not control how it is distributed, part of the therapeutic potential is lost.”
With the aim of overcoming these limitations, the research team developed protein-based nanomedicines capable of self-assembling into multivalent nanoparticles and selectively targeting tumor cells that overexpress the CXCR4 receptor. This receptor is involved in the progression and dissemination of numerous solid and hematological tumors, and its expression is associated with poorer clinical prognosis.
The platform used in the study is based on a protein nanovehicle presenting multiple copies of a CXCR4-targeting peptide. This multivalent architecture promotes cooperative receptor binding and preferential uptake by tumor cells, minimizing treatment accumulation in healthy tissues.
The study comparatively analyzed different strategies to attach the cytotoxic drug to the protein nanovehicle, an aspect that has traditionally been considered secondary compared with the choice of drug or therapeutic target. In this work, the researchers went a step further and evaluated site-specific conjugation strategies, which allow a single drug molecule to be anchored at strategically selected positions within the protein structure.
The results demonstrated that controlling both the number of drug molecules and their exact location positively impacts the ability of the nanoconjugate to accumulate in the tumor and, ultimately, its antitumor efficacy. “We observed that placing the drug in a structurally neutral region improves its therapeutic performance,” comments Dr. Unzueta.
To rigorously evaluate the real impact of this design strategy, the study combined different types of complementary experiments, ranging from cellular assays to animal models of disseminated tumor disease. This stepwise approach made it possible to establish a direct relationship between the molecular design of the nanoconjugate and its biological behavior.
First, the researchers conducted in vitro cytotoxicity assays in tumor cell lines overexpressing the CXCR4 receptor. These experiments allowed direct comparison of the antitumor potency of the different nanoconjugates under controlled conditions. The results indicated that the optimized nanoconjugate, with a single drug molecule located in a structurally neutral region, matched or surpassed the efficacy of versions with higher cytotoxic loads, while also confirming that the effect remained CXCR4-dependent.
Therapeutic efficacy was subsequently confirmed in animal models of hematological cancer, which more faithfully reproduce the complexity of the disease. In these models, the optimized nanoconjugate controlled tumor progression similarly to versions containing up to four times more drug.
“What is most relevant is that this effect is maintained when we move from the laboratory to the whole animal,” emphasizes Dr. Unzueta. “This indicates that the benefit of the design is not only theoretical but translates into greater real-world efficacy and the possibility of reducing doses.”
The study builds on a sustained research line at IR Sant Pau, developed by the Oncogenesis and Antitumor Drugs group, focused on the CXCR4 receptor as a therapeutic target in cancer. In this context, the work now published in Materials Today Bio represents a step forward by refining the design of these nanoconjugates and demonstrating that the drug conjugation strategy is decisive for maximizing efficacy. Even when maintaining the same therapeutic target.
“This study not only confirms that CXCR4 is a highly powerful target but also demonstrates that optimizing how the drug is delivered allows us to achieve greater effect with lower doses, which is one of the main goals of precision oncology,” adds Dr. Unzueta.
Overall, the work positions the conjugation strategy as a central element in the design of precision oncology therapies and reinforces the potential of multivalent protein nanomedicines as a promising alternative to conventional targeted therapies. The authors hope that these advances will provide the basis for future optimizations and preclinical studies aimed at clinical application, with the ultimate goal of offering more effective, selective, and safer treatments for patients with cancer.
Rueda A, Garcia-Leon A, Arena LA, Mendoza JI, Aviñó A, Fabrega C, Eritja R, Paez D, Alba-Castellon L, Vazquez E, Villaverde A, Mangues R, Casanova I, Unzueta U. Conjugation strategy shapes antitumor efficacy and enables dose-sparing in non-antibody protein nanoconjugates. Mater Today Bio 2026;36:102698. https://doi.org/10.1016/j.mtbio.2025.102698
