Miniaturized subcutaneous cellular implants for sustained therapeutic protein delivery in resource-limited settings.

Cell encapsulation offers a promising strategy for sustained therapeutic protein delivery, obviating the need for repeated injections. Among potential implantation sites, the subcutaneous space is particularly attractive for its accessibility and amenability to minimally invasive procedures. However, performance of subcutaneous devices reported to date has been limited due to various challenges including foreign body response (FBR) and inadequate mass transfer. Moreover, typical encapsulation devices require surgeries for implantation and retrieval, limiting their potential use in resource-limited settings. Here we present a miniaturized cell encapsulation platform comprising cells engineered to produce therapeutic proteins and an FBR-mitigating zwitterionic polyurethane nanofibrous membrane, in a thin cylindrical form factor compatible with applicator-based minimally invasive implantation and retrieval. Clonal mesenchymal stromal cells engineered to produce PGT121, a broadly neutralizing anti-HIV-1 antibody, were encapsulated and inserted subcutaneously, achieving long-term cell survival and sustained serum PGT121 concentrations for up to 36 weeks across multiple murine models. Cell-loaded devices retained therapeutic function after cryopreservation, supporting their potential use as an off-the-shelf product that can be centrally manufactured and implanted on-site without specialized infrastructure. The custom-designed applicator-based implantation and minimally invasive retrieval procedures were demonstrated in a more clinically relevant minipig model. These mini-"cellular factories" represent a translatable strategy for sustained delivery of biologic drugs in resource-limited settings.