2. Academic Validation
  3. Controlled delivery of STING agonist and manganese ion in injectable PLGA implants for enhanced cancer immunotherapy

Controlled delivery of STING agonist and manganese ion in injectable PLGA implants for enhanced cancer immunotherapy

  • J Control Release. 2026 Jan 10:389:114410. doi: 10.1016/j.jconrel.2025.114410.
Swetha Kodamasimham 1,  Helen H Ju 1,  Xingwu Zhou 1,  Yusuf Haggag 2,  Clara Huang 3,  Brianna Ha 4,  Daria Salamevich 1,  Young Seok Cho 1,  Qi Wu 1,  Steven P Schwendeman 5,  James J Moon 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI 48109, USA.
  • 2 Department of Pharmaceutical Sciences, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI 48109, USA; Department of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
  • 3 Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • 4 Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • 5 Department of Pharmaceutical Sciences, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].
  • 6 Department of Pharmaceutical Sciences, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].
PMID: 41241014 DOI: 10.1016/j.jconrel.2025.114410
Abstract

The cGAS-STING pathway plays a central role in innate immune sensing of Cancer and represents a promising target for Cancer Immunotherapy. We previously demonstrated that nutritional metal ions, such as manganese (Mn2+), can potentiate cGAS-STING signaling, amplifying IFN-I responses and driving innate and adaptive anti-tumor immunity. Here, we expand on this concept by developing a controlled-release CDA-Mn2+ PLGA milli-cylinder implant, designed for a single dose treatment for Cancer Immunotherapy. Using solvent-extrusion, we formulated poly(D,l-lactide-co-glycolide) (PLGA) 50/50 milli-cylinder implants (I.D. = 0.8 mm) loaded with cyclic di-adenosine monophosphate (CDA) and Mn2+, achieving high encapsulation efficiency and tunable, sustained release kinetics. In the murine CT26 colon carcinoma model, a single intratumoral injection of the CDA-Mn2+ PLGA implant induced robust tumor regression and extended animal survival. Mechanistically, the implant reprogrammed the tumor microenvironment and lymphoid tissues, promoted macrophage repolarization, enhanced dendritic cell priming, and significantly increased memory T-cell recruitment. One major limitation of STING-based therapies is the need for frequent intratumoral injections, which hinders patient adherence and increases clinical burden. The CDA-Mn2+ PLGA implant provides a minimally invasive, patient-centric solution for the sustained co-delivery of multiple small-molecule immune adjuvants, eliminating the need for repeated injections while maintaining therapeutic efficacy. These findings highlight a scalable, cost-effective approach to STING-targeted Cancer Immunotherapy, with the potential to broaden clinical applications and improve long-term patient outcomes.

Keywords

Cancer immunotherapy; Controlled release; Implants; Manganese; PLGA; STING.

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