*Purpose: Organ transplant is a highly successful therapy for patients facing end stage organ failure. However, there is a severe lack of transplantable organs which is exacerbated by the general decline in health of our donor population. One solution to this problem is to develop new therapeutic strategies to render marginal organs more resistant to injury, enabling their use without sacrificing the patient outcome.

*Methods: Pre-transplantation, normothermic machine perfusion (NMP) can be used to deliver targeted nanoparticles (NPs) to potentially protect the organ from post-transplant reperfusion injury by providing a prolonged release of the encapsulated therapeutic without off-target toxicity. The standard targeting approach, using amine-coupling chemistry to bound antibodies (Ab) to the surface of NPs, has two major drawbacks: 1) Random Ab orientation, which compromises targeting efficacy; and 2) Lack of adaptability, which severely stunts design optimization. To overcome these limitations, we developed a novel Ab linker technology based on a synthetic binding protein or “Monobody” (Mb). The Mb binds to the Fc region of a targeting Ab and is engineered with a terminal cysteine to enable high-efficiency conjugation to the NP surface. This approach ensures optimal Ab orientation and is easily adaptable to different targeting molecules.

*Results: Our new formulation has already shown a dramatic improvement on NP targeting efficacy in vitro and ex vivo. Indeed, with the exact same NPs and anti-CD31 Ab, the binding efficiency using the Mb-linker technology is up to 300x better than using the standard approach (measure by flow cytometry). Additionally, by targeting the Fc portion of the Ab, the system may be readily adapted to use different Abs of the same isotype (anti-CD31, anti-ICAM2, or anti-CD34) and does not require re-engineering every targeting Ab as is necessary with other existing conjugation chemistries (e.g. click chemistry). The other advantage of our Mb-linker technology combine to NMP is our ability to develop the formulation directly for human organs and then easily change the anti-human Ab for an anti-pig Ab in order to use the pig transplantation model to evaluate the long-term efficacy of the formulation.

*Conclusions: In short, we developed a new way to target nanomedicines to the cells with a profound improvement in efficacy over the current state of the art.

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