Ajinkya Kure*
Aishwarya Jadhav
Recently, the domain of drug delivery has undergone significant transformations, evolving from traditional dosage forms to cutting-edge “smart” systems that enable precise control over timing and location for therapeutic release. Standard formulations such as tablets, injections, or transdermal patches primarily rely on passive release methods and often face considerable challenges, including non-specific distribution throughout the body, insufficient concentrations at the desired target site, increased systemic side effects, and reduced compliance from patients [1]. To tackle these challenges, stimuli-responsive drug delivery systems (SRDDS) have been developed as an encouraging type of nanocarrier that modulates drug release in reaction to internal (endogenous) or external (exogenous) stimuli. Diseased tissues often exhibit unique changes in their microenvironment, such as acidic pH levels in tumours or inflamed areas, elevated enzyme activity, hypoxia, redox imbalances, and varying temperatures. By capitalising on these signals, SRDDS can maintain stability while circulating in the body and deliver their payload specifically at the target site, enhancing therapeutic precision and minimising off-target side effects [2]. Moreover, external factors such as light, magnetic fields, ultrasound, and electric fields offer an extra layer of precision, enabling on-demand control over drug release that can be activated by either a clinician or a patient with high spatial and temporal accuracy. Advanced materials such as polymers, hydrogels, liposomes, dendrimers, and metal-organic frameworks (MOFs) have been researched extensively for the creation of these sophisticated systems [3]. Recent studies have revealed multifunctional stimuli-responsive drug delivery systems (SRDDS) that can simultaneously react to multiple stimuli such as pH alongside redox or temperature combined with enzyme levels, providing synergistic control for managing complex illnesses like cancer and diabetes. For example, researchers are creating peptide-based and ionic-liquid polymer hybrid hydrogels designed for the co-delivery of anticancer medications and imaging agents, aiming to enhance both therapeutic outcomes and diagnostic results [4]. Although there have been notable advancements, several challenges, including the biocompatibility of carriers, stability, recognition by the immune system, premature drug release, and the potential for large-scale manufacturing, still impede their clinical usage. Furthermore, while numerous reviews have analysed the mechanisms of stimuli responsiveness, fewer have focused on how stimuli-responsive drug delivery systems (SRDDS) can be successfully adapted for administration via various routes (oral, ocular, transdermal, nasal, pulmonary, and parenteral), with each path presenting distinct physiological hurdles and possibilities [5]. Thus, this review aims to (i) classify different stimuli and their associated drug release mechanisms, (ii) explore the development and effectiveness of SRDDS for various administration pathways, and (iii) highlight emerging trends, challenges, and future prospects in the field of stimuli-responsive and multi-route drug delivery systems.
- Classification of Stimuli:
Stimuli-responsive drug delivery systems have either endogenous (internal) triggers, those inherent to tissue or cellular environments, or exogenous (external) triggers applied from outside the body. These stimuli dictate carrier behaviour (swelling, degradation, link-cleavage, conformational change) and thereby the controlled release of therapeutic agents.
10.5281/zenodo.17980253