Controlled Functionalization of Poly(Glycerol Adipate) With <i>N</i> ‐Acetyl‐Tryptophan Enables the Design of Dry Powder Nanoparticle Formulations

ABSTRACT Poly(glycerol adipate) (PGA) is a glycerol‐based biodegradable polyester that is emerging as a versatile platform for healthcare applications, owing to its biocompatibility, ease of functionalization, tunable physicochemical properties, and potential for enzymatic synthesis via green chemistry protocols. However, PGA is a viscous liquid with low glass transition temperature (~ T g −30°C) which limits its use in dry powder‐based medicines formulations for inhalation or reconstitution for injection. Here, we report an efficient synthetic strategy that exploits the pendant hydroxyl groups on the PGA backbone to achieve &gt; 90% functionalization with N ‐acetyl‐tryptophan (NAcTrp). This approach enables precise tuning of the T g and hydrophobicity (water contact angle) of PGA‐NAcTrp polymers (60%–100% target substitution), with both properties exhibiting a strong linear correlation to the degree of NAcTrp functionalization. This strategy achieves T g values in the 40°C–63°C range, making these materials suitable for dry powder formulations. The synthesized PGA‐NAcTrp 60%–100% polymers can be formulated into spherical nanoparticles with a sub‐100 nm particle size, which, using trehalose (5% w/v) as a cryoprotectant in the freeze‐drying process, can be successfully reconstituted into nanoparticles suspensions. Overall, this study broadens the applicability of functionalized PGA polymers, establishing their potential for designing and fabricating dry powder particle‐based formulations across diverse healthcare applications.