The Stability–Release Paradox in Long-Acting Peptide and Protein Delivery: A Review of Material–Cargo Compatibility and Therapeutic Integrity

Long-acting peptide and protein delivery requires more than prolonged release; the therapeutic must remain chemically, physically, structurally, and functionally competent throughout processing, depot residence, and release. This review examines the stability–release paradox, in which material features introduced to extend residence can also alter cargo integrity. Rather than cataloging platforms or restating the need for biologic stabilization, the literature is organized around a cargo-specific compatibility question: whether a retention mechanism, depot microenvironment, and intended residence time remain compatible with preservation of therapeutic attributes required for activity. Published experimental studies and recent reviews available through 10 August 2026 were critically examined, with emphasis on poly(lactic-co-glycolic acid) (PLGA) systems, hydrogels, affinity-based depots, self-assembling formulations, and translational studies linking release with stability or pharmacological performance. Across these platforms, integrity is influenced by hydration, microclimate pH, reactive degradation products, drug–material affinity, interfacial exposure, local concentration, molecular crowding, processing stress, and host–depot interactions. Experimental studies of degradable polyesters show that prolonged mass release can coexist with peptide acylation or other chemical changes, whereas hydrogel and affinity systems demonstrate that reversible retention can suppress premature escape but still requires cargo-specific verification of recovery and biological function. The review therefore frames long-acting formulation design around three linked considerations: the depot as a dynamic pharmaceutical microenvironment, therapeutically competent release as an endpoint beyond cumulative mass recovery, and residence-time–stability matching as a compatibility test between planned confinement and the cargo’s demonstrated stability window. This framework supports material selection and evaluation based on therapeutic integrity, stability-indicating release measurements, clinically relevant loading, and pharmacokinetic/pharmacodynamic (PK/PD) evidence appropriate to the therapeutic claim.