Aliphatic Poly(Carbonate)s with Acid Responsive Release Mechanisms for Micellar Anti-Tumor Drug Delivery

Micellar drug delivery systems have emerged as a versatile platform for improving the solubility, stability, and targeted release of chemo(immuno)therapeutics. This review focuses on micellar formulations that combine two key design principles: the inherent biodegradability of aliphatic poly(carbonate)s and the universal acid-responsive trigger mechanism. These systems are particularly attractive for tumor therapy, where the acidic microenvironment can be exploited for controlled drug release. We differentiate between two major classes: (i) systems employing acid-labile linkages for reversible conjugation of pharmaceutically active compounds, and (ii) systems in which micelle disassembly or polymer backbone degradation is governed by acid-responsive functionalities. Both categories are systematically evaluated according to the chemical motifs enabling acid sensitivity, including oximes, imines, hydrazones, boronate ester, acetals, ketals, and tertiary amines, among others. The review highlights recent advances in synthetic strategies, structure-property relationships, and therapeutic performance, emphasizing how these design elements synergistically enhance drug loading, release kinetics, and biocompatibility. Finally, we discuss current challenges and future directions for translating these smart micellar systems into promising tumor-targeted (immuno-)therapeutics.