The Role of Biofunctional Polymers in Polymer–Drug Conjugates: From Passive Carriers to Therapeutically Active Platforms

Abstract

Polymer–drug conjugates (PDCs) represent an advanced drug delivery strategy designed to address critical limitations of conventional therapeutics, including poor water solubility, rapid systemic clearance, and off-target toxicity. By covalently linking therapeutic agents to polymeric carriers through rationally designed linkers, PDCs enable improved pharmacokinetic profiles, enhanced stability, and controlled drug release. This review provides a comprehensive overview of the key design principles governing PDC systems, with a particular focus on the role of biofunctional polymers. Essential parameters for polymer selection, including biocompatibility, biodegradability, molecular weight, and functional group availability, are discussed in relation to their influence on drug loading, release kinetics, and biological performance. In addition, both natural and synthetic polymers are evaluated for their ability to improve solubility, modulate biodistribution, and reduce systemic toxicity. An overview of stimuli-responsive PDCs is provided, including pH-, redox-, and temperature-sensitive systems, which enable site-specific and spatiotemporally controlled drug release in response to pathological microenvironments. We emphasize the special role of bioactive polymers such as poly-lysine, hyaluronic acid, chitosan, and gelatin for their intrinsic biological activity, including receptor-mediated targeting, antimicrobial activity, and synergistic therapeutic effects. These properties support the development of dual-active conjugates with enhanced specificity and efficacy. Overall, this review underscores the transition of polymers from passive carriers to active therapeutic components and outlines current challenges and future perspectives for the clinical translation of next-generation PDCs.