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K. V. N. Naik S. P. Sanstha's, Institute of Pharmaceutical Education & Research, Nashik, 422 002, Maharashtra, India
Stimuli-responsive drug delivery systems (SRDDS), which provide regulated, accurate, and adaptive drug release in response to particular internal or external stimuli, have become a revolutionary platform in contemporary therapies. Passive diffusion, low site specificity, systemic toxicity, and uneven patient adherence are common problems with traditional delivery methods. By taking use of diseased microenvironmental characteristics including acidic pH, increased enzyme activity, hypoxia, and redox imbalances in addition to externally applied stimuli like light, magnetic fields, ultrasound, and electrical impulses, SRDDS overcomes these constraints. The development of complex carriers? hydrogels, nanoparticles, micelles, dendrimers, and metal-organic frameworks that experience physicochemical changes like swelling, contraction, phase transitions, or cleavage of labile chemical bonds to achieve triggered release has been made possible by developments in polymer science. These processes lower off-target exposure and greatly improve treatment accuracy. Clinical translation is still hampered by issues with biocompatibility, early drug leakage, immune recognition, and scalability despite significant advancements. Furthermore, there is still a lack of consolidated knowledge regarding the optimisation of SRDDS for various administration routes, each of which presents distinct physiological opportunities and barriers. This study summarises current developments in SRDDS, categorises stimuli and their release mechanisms, assesses polymeric materials utilised in the creation of smart carriers, and addresses the systems' suitability for oral, ocular, transdermal, nasal, pulmonary, and parenteral routes. Emerging directions, existing limitations, and future prospects are highlighted to support the advancement of next-generation intelligent drug delivery technologies.
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.
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.
Ajinkya Kure*, Aishwarya Jadhav, Stimuli-Responsive Drug Delivery; Mechanism and Multi-Route Application: A Comprehensive Review, Int. J. Sci. R. Tech., 2025, 2 (12), 272-283. https://doi.org/10.5281/zenodo.17980253
10.5281/zenodo.17980253