pH-sensitive proteins advance precision drugs

Researchers working on protein design have built a drug-delivery system that is meant to stay intact in normal conditions and come apart when it reaches more acidic environments inside the body. The work, described in a May 2024 study highlighted by the Baker Lab at the University of Washington, uses custom protein nanoparticles that can package molecular cargo, target selected cells and then release that cargo when pH drops. The platform is aimed at a longstanding problem in drug delivery: getting a therapy to the right cells while limiting release elsewhere. Nature Structural & Molecular Biology said the system combines several functions in one framework, including cargo encapsulation, target recognition, pH-dependent disassembly and controlled release. ### Why does acidity matter for a drug carrier? Tumors and intracellular compartments such as endosomes are often more acidic than blood and many healthy tissues. (nature.com) The Baker Lab said particles entering cells pass through acid-filled endosomes with an internal pH of roughly 4.5 to 6.5, and that the team designed nanoparticles that disassembled from pH 5.5 up to pH 6.8. (nature.com) That matters because a carrier can, in principle, remain closed while circulating near physiological pH and then open only after it reaches an acidic microenvironment. Reviews of pH-responsive delivery systems have described that strategy as a way to increase local drug release and reduce systemic toxicity, particularly in cancer applications. ### What exactly did the team build? (bakerlab.org) Erin Yang and collaborators started from an earlier antibody-containing protein nanoparticle platform that could target cells but had pores too large to hold cargo effectively, according to the Baker Lab. To fix that, the team designed protein “plugs” that fill those openings and convert the particles into enclosed delivery vehicles. (pubs.rsc.org) The resulting system is modular. The Baker Lab said the particles are assembled from three separately purified protein building blocks, and one antibody-related component can be swapped from a small Fc fragment to a full-sized antibody while preserving the overall structure. That design is intended to let researchers retarget the same basic carrier toward different cell-surface receptors. (bakerlab.org) ### How is the pH response engineered into the proteins? The pH-triggered behavior is built into the amino-acid sequence of the plug proteins. The Baker Lab said the team used Rosetta, a computational protein-design platform, to tune those sequences for stronger pH responsiveness. Nature’s research briefing said targeted biologics delivery requires protein nanomaterials that can do multiple jobs at once inside a single structure. (bakerlab.org) In this case, the pH-sensitive elements are meant to destabilize the particle only under selected chemical conditions, rather than causing constant leakage. ### What evidence did the researchers show? In one experiment, the Baker Lab said fluorescent proteins trapped inside the nanoparticles were released after researchers shifted the surrounding environment from neutral to acidic. (bakerlab.org) That result showed the particles could hold cargo and then unload it in response to a pH change. The study was presented as a platform technology rather than a clinical product. (nature.com) The available summaries do not give a clinical timeline, dosing plan or human trial schedule. ### Where could this be used next? Cancer is one obvious target because solid tumors often contain acidic regions, and the Baker Lab explicitly said the disassembly range overlaps with acidity observed around tumors. More broadly, the lab said the approach could be used to transport therapeutic proteins, small molecules or CRISPR components into living cells. (bakerlab.org) (nature.com) The next milestones are still preclinical. The Baker Lab said future work will focus on improving how efficiently different cargoes are packaged and measuring delivery efficiency to tumors in animal models. (bakerlab.org)