Semaglutide attached to hydrogel microspheres achieved a 36-day release half-life in mice, producing equivalent weight loss to twice-daily dosing and potentially enabling once-monthly human administration with a lower peak-to-trough ratio.
36-day half-lifeA single injection of hydrogel microsphere-semaglutide released the drug over 36 days in mice, matching the weight loss of twice-daily semaglutide
What the researchers found
Hydrogel microsphere-semaglutide showed an in vivo release half-life of ~36 days in mice. A single subcutaneous dose produced 20% lean-sparing body weight loss over one month, statistically equivalent to twice-daily semaglutide. Pharmacokinetic simulations predicted once-monthly human dosing with Cmin matching weekly dosing but only 75% of the Cmax, potentially reducing adverse effects.
Why it matters
Weekly semaglutide injections are a barrier for some patients. A monthly formulation that maintains the same therapeutic minimum while reducing peak drug levels could improve adherence and potentially reduce the gastrointestinal side effects (nausea, vomiting) that cause many patients to discontinue treatment.
The numbers in context
Cleavable linker designed for ~1 month in vivo release half-life. Single subcutaneous dose tested in mice.
How the study worked
Semaglutide conjugated to hydrogel microspheres via a cleavable linker (designed for ~1 month release half-life). Single subcutaneous dose administered to diet-induced obese mice. Pharmacokinetic parameters and bodyweight measured. Results used to simulate human PK for once-monthly dosing. Compared to semaglutide administered twice daily in mice.
Who was studied
Mouse pharmacokinetic and weight loss study
What this study cannot tell us
Mouse study — PK translation to humans is estimated, not proven. The 'lean-sparing' weight loss claim needs verification in human metabolic studies. Manufacturing scalability of hydrogel microspheres not demonstrated. Long-term safety of the hydrogel carrier not assessed. Human clinical trials needed.
How to read the evidence
Rated preliminary: proof-of-concept mouse study with PK simulations for humans. No human clinical data. Published in PNAS, lending credibility to the approach.
When this study was published
Published in 2024 in PNAS. Represents a significant advancement in long-acting peptide formulation technology.
The bigger picture
This addresses one of the major limitations of current GLP-1 peptide therapy — injection frequency. If once-monthly dosing can match weekly efficacy while reducing peak-related side effects, it could expand the patient population willing and able to use these transformative medications.
Questions still open
- Will the predicted lower Cmax actually translate to fewer GI side effects in humans?
- Could this technology enable even less frequent dosing (every 2-3 months)?
- How does the manufacturing cost of hydrogel microsphere formulations compare to standard injectable semaglutide?
Common questions
Could semaglutide become a once-monthly injection?
Would monthly semaglutide have fewer side effects?
Read the original research
The limitation of lipidation: Conversion of semaglutide from once-weekly to once-monthly dosing.
Proceedings of the National Academy of Sciences of the United States of America, 121(47), e2415815121
Citation
Schneider, Eric L; Hangasky, John A; Fernández, Rocío Del Valle; Ashley, Gary W; Santi, Daniel V. (2024). The limitation of lipidation: Conversion of semaglutide from once-weekly to once-monthly dosing.. Proceedings of the National Academy of Sciences of the United States of America, 121(47), e2415815121. https://doi.org/10.1073/pnas.2415815121