(1) Background: Modern pharmacology and regenerative medicine seek effective, safe drug delivery systems that allow for the controlled and sustained release of active ingredients; in situ forming implants (ISFIs) represent one such option. Systems based on poly(lactic-co-glycolic acid) (PLGA) and the solvent N-methyl-2-pyrrolidone (NMP) offer a safe, biodegradable, and non-invasive alternative. (2) Methods: ISFIs were prepared using NMP and PLGA at 50:50 and 85:15 ratios, combined with the supernatant obtained from umbilical cord Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs). Cellular utility, cytotoxicity, cell proliferation, and in vivo biocompatibility were evaluated using Annexin, 7AAD, Calcein, and PrestoBlue assays, as well as a murine model. Statiscal significance was determined using one way ANOVA followed by Tukey’s post hoc test for multiple comparisons, with the significance level at p < 0.05. (3) Results: Differences in cumulative release profile were observed between the PLGA/NMP 50:50 and 85:15 formulations. PLGA 50:50 exhibited higher early and cumulative release of WJ-MSC-supernatant-derived material, whereas PLGA 85:15 showed a slower and more sustained release profile. (4) Conclusions: Cell-free therapy delivered via PLGA 50:50/NMP ISFIs, incorporating associated immunomodulatory factors as supernatant’s WJ-MSCs, is suitable for an effective controlled-release system.