SUMMARY The lysosomal storage (LSDs) disorders comprise ~50 fatal diseases due to genetic lysosomal enzyme deficiency, which affects most tissues and associates to broad inflammatory phenotype. Treatment is by enzyme replacement therapy (ERT), where recombinant enzymes are i.v. infused in hospitals, with high burden to patients and the health system (≥$150,000/patient- year). Still, ERT success is restricted to a few diseases that affect the liver, spleen, and kidneys, since the enzymes access these blood clearance organs. Yet, delivery to tissues separated from the blood by a tight endothelial barrier (mainly the brain, to some extent the lungs) is hindered. An example is that of types A-B NPD, a sphingomyelin storage due to acid sphingomyelinase (ASM) deficiency, which leads to premature death. NPD-A has a strong neurological involvement, not improved by ERT. NPD-B mainly affects the lungs and, although helped by ERT, high and frequent dosage causes immune reactions and resistance, along with other side effects. Our original award focused on targeting recombinant ASM to ICAM-1, a protein overexpressed in inflammation and associated to a new route of transport across the endothelium and into lysosomes of tissue cells. Through the previous period we successfully achieved our goals and improved: brain and lung targeting, transport across the endothelium, uptake in subjacent tissue cells, lysosomal enzyme activity, and substrate reduction (38 articles, 5 journal covers and/or editorials, 17 awards). To move this promising platform toward translation, we now will focus on: (a) enzyme encapsulation in biodegradable polymer nanocarriers and safer targeting moieties to minimize immune recognition, (b) incorporation of anti-phagocytic signals to minimize clearance, (c) tuning of the formulation parameters to optimize the balance between brain-lung targeting and explore combination therapy for enhanced effects, and (e) optimization of carrier degradation within lysosomal to avoid “polymer storage” upon chronic treatment. We have key results supporting these new directions and completion of a renewed project will significantly advance the opportunity for a more effective and safer treatment of NPD, and likely other LSDs.