91 Quick summary: Researchers have proposed a novel paradigm that reframes the protein corona from an problematic biological obstacle into a programmable navigation interface capable of guiding nanomedicines across the highly restrictive blood-brain barrier. By strategically engineering particle surface chemistry to capture specific plasma proteins, these nanoscale carriers can actively utilise natural receptor mediated transport pathways to improve delivery outcomes for severe neurological diseases like Alzheimer’s and glioblastoma. For healthcare practice and public policy, this shift towards precision corona design offers a vital roadmap to make neurotherapeutics more predictable and effective, potentially transforming the clinical treatment and well-being of millions of patients suffering from complex brain conditions worldwide. The blood–brain barrier is one of the body’s most effective protective interfaces, keeping harmful substances away from the brain while also blocking many medicines from reaching brain tissue. This remains a major challenge for treating neurological diseases including Alzheimer’s disease, Parkinson’s disease, and malignant glioma. Nanomedicines offer one possible route forward because they can be designed to interact with natural transport pathways at the barrier. Yet their performance in the body is often difficult to predict. A nanocarrier that looks precisely engineered in the laboratory may look very different once it enters the bloodstream, where proteins rapidly attach to its surface and form what is known as a protein corona. This layer can hide engineered targeting ligands, introduce new biological signals, or redirect the carrier toward clearance organs. In a new Perspective published in Science Bulletin, researchers Changjian Xie, Iseult Lynch, Chunying Chen, and Zhiling Guo argue that the protein corona should not be treated only as an unwanted coating. Instead, they propose that it can act as a dynamic navigation interface that shapes how nanomedicines are recognised, internalised, sorted, and released across the blood–brain barrier. The article moves the discussion beyond passive leakage, which in many brain diseases is limited, heterogeneous, or unreliable. Receptor-mediated transcytosis provides a more physiologically relevant route, coupling recognition at the endothelial surface with directional transport through the cell. The authors emphasise that successful delivery depends not only on uptake but also on the intracellular pathway that follows. The Perspective organises protein corona behavior into five connected stages: circulatory screening, receptor binding, internalisation, intracellular trafficking, and release on the brain side. During circulation, coronas rich in immune proteins may promote rapid clearance, while those enriched in selected dysopsonins or receptor-facing proteins may extend circulation and improve the chance of blood-brain barrier engagement. At the endothelial surface, corona components such as apolipoproteins or transferrin may help connect nanocarriers with receptors including LRP1 and the transferrin receptor. After internalisation, the corona continues to change. Blood-derived proteins can be replaced or supplemented by proteins from endocytic and cellular compartments, and this remodeling may determine whether a carrier is recycled back to the blood, sent to lysosomes for degradation, or transported toward release on the brain side. The authors highlight intracellular sorting and polarised exocytosis as central design challenges for brain-targeted nanomedicine. The article reviews several strategies for manipulating the corona, including tuning particle size, surface chemistry, and lipid composition to bias the corona that forms in vivo. Another approach is recruitable corona engineering, in which nanocarriers are designed to capture functional endogenous proteins in blood and use them as biological bridges to endothelial receptors. Biomimetic pre-coating and shielding strategies may also help extend circulation while preserving receptor access needed for transport. Several bottlenecks remain. Only a small fraction of injected nanomedicine typically reaches diseased tissue, and brain delivery faces additional constraints from the blood-brain barrier, blood-tumour barrier, and active efflux systems. Rodent models may overestimate delivery potential, stimulus-responsive carriers may release their payload too early in off-target tissues, and long-term safety, anti-PEG immune responses, and scalable quality control also require closer attention. Glioblastoma presents a particularly difficult case. The disease contains regions with an intact blood-brain barrier alongside regions with a more permeable blood-tumour barrier, creating uneven nanomedicine exposure within and between lesions. The authors suggest that future development will need more informative models and trial designs combining molecular profiling with biodistribution, pharmacokinetic, and imaging readouts. Looking ahead, the authors call for precision corona design, where future nanocarriers may need to be matched to patient-specific plasma protein fingerprints and disease states. Near-native corona capture, top-down proteomics, molecular dynamics simulation, artificial intelligence-assisted prediction, brain organoids, and blood-brain-barrier-on-a-chip systems could together turn the protein corona into a measurable and programmable quality attribute for brain delivery. By reframing the protein corona as a stage-aware and potentially programmable interface, the Perspective provides a roadmap for making blood-brain barrier transcytosis more predictable, controllable, and clinically relevant, with potential benefits for millions affected by Alzheimer’s, Parkinson’s, and brain tumours worldwide.