We present the SWAP design, a novel, structurally cohesive IGF2-based tag for modular receptor targeting during gene therapy for lysosomal storage disorders (LSDs). We found that IGF2’s central loop is critical for high-affinity binding to the insulin receptor (IR) and IGF1 receptor (IGF1R)—both involved in glucose homeostasis—but is not required for interaction with the cation independent mannose 6-phosphate/IGF2 receptor (CI-M6P/IGF2R)—a key target for lysosomal delivery. This formed the basis for designing the Substitution of the central-loop With Augmenting Peptides (SWAP) tag. By replacing the central loop with alternative epitopes, SWAP ensures high-affinity multimodal receptor targeting while maintaining structural integrity. In vivo, lentiviral gene therapy employing IDS fused to SWAP variants containing ApoE and RAP12x2 inserts corrected Hunter disease pathology across multiple tissues, including liver, spleen, heart, bone, and brain, matching the efficacy of the traditional IGF2 tag. These findings position SWAP as a novel and effective tag design for IGF2-based therapeutics with a more favourable ligand–receptor interaction.

Background: Trimethyltin (TMT)-induced neurodegeneration leads to molecular and behavioral changes resembling those of Alzheimer’s disease (AD), making it a relevant model for investigating potential therapeutic interventions. Continuous theta burst stimulation (cTBS) has shown promise in psychiatric and neurological disorders but remains largely unexplored in AD models. Methods: Adult male Wistar rats were divided into four experimental groups: intact, TMT (8 mg/kg, ip) and TMT treated with cTBS or a sham protocol for three weeks. The open field test and novel object recognition test were used to assess anxiety-like behavior, memory, and learning, respectively. The extent of microgliosis in the hippocampus was assessed by immunohistochemistry, while protein expression was estimated by Western blot. Results: cTBS improved TMT-mediated changes in anxiety-like behavior, learning, and memory and reduced microgliosis in the CA1 hippocampal region. Both TMT and cTBS affected NMDAR subunits, with the most significant finding being a cTBS-mediated decrease in NR2B, which was previously increased by TMT. Conclusions: These are the first data on the beneficial effects of cTBS on behavioral and molecular changes in a model of neurodegeneration that mimics some of the key aspects of AD pathology. Further research is needed to clarify the therapeutic potential of cTBS in AD treatment.