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.
Figure 1. Classification of Stimuli
The biomaterials that respond to pH levels detect variations in pH and experience physical and chemical alterations in their polymer chains, initiating the release of the drug. These materials are predominantly utilised for drug release triggered by pH changes compared to other types of stimuli. The conventional pH-responsive carriers exhibit their effectiveness based on the pH levels found in various organs, such as the stomach and intestines [6]. pH-sensitive polymers can be classified as either polyacids, which detect and release at alkaline pH, or polybases, which respond to acidic pH and release the drug. Eudragit S100 is a pectin nanoparticle coated with citrus that specifically aims to deliver the anticancer drug, 5-Fluorouracil, to the colon [7]. Carriers designed for this purpose can detect changes in pH levels at particular disease locations, such as ischaemic tumour areas and inflamed tissues. Additionally, they can distinguish pH variations in different organelles, such as lysosomes and endosomes. Healthy tissue typically maintains an extracellular pH of 7.4, while in solid tumours, the pH drops to 7.0 due to an increased rate of glycolysis. This lower pH present in tumours serves as a trigger for controlled drug delivery systems [8,9]. The pH stimulus can be paired with other triggers, including redox conditions and temperature, to ensure targeted release at specific sites, such as poly(2-(diisopropylamino) ethyl methacrylate) (PDPAEMA) [8].
Enzymes serve as catalysts in drug delivery systems. They possess distinct characteristics such as specificity to their substrates and a high degree of selectivity under mild conditions. Given their close association with biological and metabolic functions, enzymes can facilitate the targeted release of drugs at sites of inflammation. A significant challenge in utilising enzyme-responsive drug delivery systems is the need for precise control over the initial release phase. These systems are classified based on their interactions with effector molecules [10]. Enzymes like glycosidases, lipase, phospholipases, and proteases are involved in nearly all biological and metabolic processes, making them useful for facilitating drug release through enzyme-mediated mechanisms in cancerous or inflamed tissues [11].
1.1.3 Redox-Responsive Systems
The alteration in redox potential initiates the release of drugs from redox-sensitive biomaterials. These materials are commonly utilised in disease treatment through intracellular drug delivery mechanisms. The redox potential differs across various tissues in microenvironments, which is beneficial for the development of redox-sensitive drug delivery systems [12]. The reduction of glutathione (GSH) is a widely recognised redox system found in cancer cells. While GSH concentrations in blood and normal extracellular matrices are noted to be between 2 and 20 μM, levels within cancer cells vary from 2 to 10 mM, representing an increase of 100- to 500-fold compared to normal levels. The substantial disparity in GSH levels between cancerous and normal cells has rendered redox-responsive delivery systems an appealing approach for designing drug delivery systems aimed at targeting specific intracellular sites within tumours [13].
1.1.4 Temperature-Responsive Systems
Temperature serves as the trigger for the release of drugs. Thermo-responsive polymers feature a lower critical solution temperature (LCST). When the temperature is below LCST, these polymers are soluble, hydrated, and tend to swell, which is the state during drug loading. Conversely, when the temperature exceeds LCST, these polymers shrink and dehydrate, leading to drug release. An example of a thermosensitive polymer that demonstrates these properties is poly (N-isopropyl acrylamide) [14].
Light activation enables precise regulation of drug release both spatially and temporally. Near-infrared (NIR) light is more effective at penetrating tissues than UV or visible light and is frequently used in NIR-responsive nanocarriers. The mechanisms involved include the breaking of photochemical bonds, photo-isomerisation (as seen with azobenzene and spiropyran), and photothermal effects. A recent review centred on metal–organic framework (MOF)-based carriers emphasises the significance of light-triggered release, alongside sensitivity to internal stimuli. Critical design considerations encompass wavelength penetration, phototoxicity, thermal management, and safe usage in living organisms [15].
In drug delivery systems that respond to magnetic fields, the release of medication can be controlled remotely by using an external magnetic field. These magnetic systems consist of a drug carrier, such as nanoparticles, and materials like magnetite (Fe?O?), maghemite (α-Fe?O?), iron, nickel, cobalt, and samarium-cobalt, which react to an applied magnetic field. The magnetic characteristics of these materials are determined by their magnetic susceptibility, which is the ratio of the induced magnetisation to the applied magnetic field [16].
Ultrasound can induce cavitation, produce shear forces, facilitate acoustic droplet vaporisation, or generate localised heat, all of which can enhance delivery systems or improve the permeability of tissues. A recent pre-print discusses how employing microbubbles to generate cyclic jetting in the presence of ultrasound can breach cell membranes and enhance cellular uptake, suggesting that ultrasound-sensitive carriers are progressing towards improved mechanistic accuracy [17].
Electrical stimulation can trigger redox reactions, ion movement, changes in polymer shape, or variations in swelling in electro-responsive materials. These technologies are often employed in implantable or wearable devices, where an applied voltage regulates drug release. Although they are not yet commonly used in clinical settings, these systems are gaining traction for transdermal patches and implantable delivery methods [18].
Polymers capable of altering their characteristics in reaction to external or internal stimuli are gaining attention as a promising basis for drug delivery systems. Polymeric nanoparticles can help reduce the toxicity of medications, enhance the circulation of hydrophobic drugs, and boost a drug's effectiveness. Additionally, polymers that react to particular stimuli can be utilised to facilitate the controlled release of drugs into targeted regions of the body [19].
A defining and distinguishing trait of pH-responsive polymers is the existence of either acidic or basic groups, which function to either accept or release protons when there is a shift in pH.
Natural origin polymers:
Synthetic polymers:
This collection of materials reacts to variations in ionic conditions in the environment. They demonstrate reversible physical and chemical changes in response to shifts in pH or ionic concentration. An alteration in the ionic strength around these materials impacts the interactions between the solution’s ions and the polymer’s ions, resulting in swelling or dehydration. Instances of polymers that react to ions include alginate (Ca2+) and chitosan (Mg2+) [21].
Numerous redox reactions take place within the intracellular environment, including NADP+/NADPH, O?/O??O2−, and glutathione (GSH). In particular, GSH has garnered attention in the field of drug delivery. GSH’s full chemical name is γ-L-glutamyl-L-cysteinyl-glycine, and it is a peptide made up of glycine, cysteine, and L-glutamic acid. Research has shown that GSH concentrations in tumour tissue can be four times greater than in healthy tissue in mice, indicating that GSH levels make a suitable trigger for drug delivery systems [22]. The concentration of GSH is important for drug delivery because of the significant difference between its levels inside (1–10 mM) and outside the cell (1–10 μM). Doxorubicin was delivered using polymer micelles. These micelles were created with a graft copolymer of poly (acrylic acid)-g-poly (ethylene glycol) (PAA-g-PEG), which features a disulphide bond [23, 24].
As indicated by the name, temperature-responsive polymers can alter their characteristics (frequently solubility) in reaction to variations in temperature (heating or cooling) in the surrounding environment. Temperature is a factor that can be easily measured and monitored, and the systems for such measurements are well established. For this reason, it is commonly utilised in the creation of smart polymers. An example of a temperature-responsive polymer includes poly(N-isopropylacrylamide) (PNIPAAm), along with poloxamers and prolastin.
The parameters related to the evaluation of this type of polymer include:
The first polymer that was employed in the development of thermo-responsive materials was PNIPAAm (poly(N-isopropylacrylamide)). Its application is attributed to its comparable LCST temperature of 32–33°C, which is close to human body temperature [25,26].
Magnetic field-responsive polymers are materials that can alter their characteristics, including density, optical properties, and shape, when exposed to a magnetic field. These specific attributes can be achieved by incorporating magnetic particles, such as magnetite (Fe?O?) and maghemite (γ-Fe?O?), into a formulation with polymers like poly (ethylene glycol) (PEG), dextran, poly (vinyl alcohol) (PVA), and poly (ethylene imine) (PEI) [27].
Ultrasound refers to a wave generated by alternating current due to the mechanical vibrations of a piezoelectric material. Waves can be categorised based on frequency: low (<1 MHz), medium (1–5 MHz), and high (5–10 MHz). Ultrasound can influence materials in several ways: (a) thermal, resulting in a rise in temperature; (b) nonthermal, known as cavitation, where ultrasonic vibrations lead to the formation of gas bubbles. An example of a polymer that responds to ultrasound is dodecyl isocyanate-modified PEG-grafted poly (2-hydroxyethyl methacrylate), polyglycolides, or polylactides [28].
Polymers that respond to electric fields exhibit alterations in their physical properties when exposed to slight variations in electric current. The alterations in the electric field result from the transformation of electrical energy into mechanical energy.
Electro-responsive polymers include:
Table 1. Polymers used in Stimuli Responsive Drug Delivery.
|
Stimulus Type |
Definition / Mechanism |
Examples (Natural & Synthetic) |
|
pH-Responsive Polymers |
Contain acidic or basic groups that accept or donate protons when pH changes, altering solubility or swelling. |
Natural: Alginates, Hyaluronic acid, Chitosan Synthetic: Poly (acrylic acid) (PAAc), Poly (vinylphenyl boronic acid) (PVPBA), Poly (ethylene glycol acrylate phosphate) (PEGAP), Poly (vinyl sulfonic acid) (PVSA), PDMA, Poly(4-vinylpyridine) (P4VP), Poly(N-vinylimidazole) (PVI) |
|
Ion-Responsive Polymers |
Exhibit reversible physical/chemical changes (swelling or dehydration) when ionic strength or ion concentration varies. |
Alginate (responsive to Ca²?) and chitosan (responsive to Mg²?) |
|
Redox-Responsive Polymers |
Respond to intracellular redox potential, particularly high glutathione (GSH) levels, triggering drug release. |
PAA-g-PEG micelles with disulphide bonds |
|
Temperature-Responsive Polymers |
Change solubility or other properties when exposed to temperature variations. |
PNIPAAm, poloxamers, Prolastin |
|
Magnetic Field-Responsive Polymers |
Alter density, shape, or optical properties when exposed to a magnetic field due to embedded magnetic particles. |
Polymers with Fe?O? or γ-Fe?O? combined with PEG, Dextran, PVA, and PEI |
|
Ultrasound-Responsive Polymers |
Respond to ultrasonic waves via thermal effects or cavitation, enabling triggered drug release. |
Dodecyl isocyanate-modified PEG-g-PHEMA, Polyglycolides, Polylactides |
|
Electric Field-Responsive Polymers |
Show physical property changes when exposed to electrical stimulation, converting electrical to mechanical energy. |
Polypyrrole (PPy), Polyaniline (PANI), PEDOT, Chitosan |
Stimuli-responsive drug delivery systems (SRDDS) operate through a series of physicochemical and molecular interactions that convert environmental factors or externally applied triggers into detectable material responses that facilitate drug release. This process can be visualised as a succession of changes that begin with the expansion or contraction of polymers, followed by alterations in phase or bond cleavage reactions, and frequently culminating in the breakdown of nanocarriers or disruption of membranes, which ultimately results in the diffusion or release of the drug into the biological environment.
The primary and frequently reversible response of polymer networks to an external trigger is either swelling or contraction. Hydrophilic polymers take up water, which causes an increase in their mesh size, facilitating the outward diffusion of drug molecules; conversely, hydrophobic transformations or ionic crosslinking can result in contraction, expelling the drug through convective flow. The equilibrium swelling degree (Q) is influenced by the balance between the osmotic pressure exerted by the solvent inside the gel and the elastic retractive forces of the network, according to the Flory–Rehner theory. For pH-sensitive polymers such as poly (acrylic acid) or chitosan derivatives, the ionisation of their acidic or basic functional groups alters the electrostatic repulsion, resulting in changes in volume [31,32]. Thermo-responsive polymers, such as poly(N-isopropylacrylamide) (PNIPAAm), undergo coil-to-globule transitions at their lower critical solution temperature (LCST, approximately 32 °C), where enhanced hydrophobic interactions cause shrinkage. In drug delivery systems, this adjustment of swelling and shrinking has a direct impact on the diffusion coefficients. An increase in swelling enlarges pore sizes, promoting sustained release, while shrinkage can trigger pulsatile “on-off” release patterns [33].
Phase transitions are defined by abrupt structural transformations triggered by external factors. These transitions may occur as sol-gel, micelle-unimer, or liquid–solid changes. In thermo-responsive systems, the polymer’s lower critical solution temperature (LCST) or upper critical solution temperature (UCST) dictates its physical state: when the temperature falls below the LCST, the polymer chains remain hydrated and extended; when it exceeds the LCST, they contract due to the breakdown of hydrogen bonds with water. This mechanism leads to the rapid release of drugs as the matrix compacts. In the case of materials that respond to light or magnetic fields, the application of energy induces local heating or alters the conformation, triggering a phase transition that impacts permeability. For instance, gold nanorod-loaded PNIPAAm gels leverage plasmonic photothermal conversion, resulting in a swift increase in temperature and the collapse of the gel when exposed to near-infrared light, aiding the controlled release of anticancer drugs. Similarly, block copolymers like PEG–PLGA–PEG experience a sol–gel transition at body temperature, allowing injectable formulations that solidify in situ for extended release [34,35].
An essential feature of SRDDS is the inclusion of reactive chemical linkers between the drug and the carrier or within the polymer matrix that can be selectively broken by specific stimuli.
Typical labile bonds consist of:
Upon cleavage, either the polymer loses its structural integrity or hydrophilicity, or the bond between the drug and the linker is severed, resulting in the release of the therapeutic agent. This mechanism provides .high chemical specificity, as the release occurs solely in the presence of the specific trigger. Recent studies from 2024–2025 have indicated the creation of multi-responsive polymers where drug release is governed by both pH and redox stimuli through the sequential cleavage of hydrazone and disulphide bonds, achieving accurate timing and location control in tumour microenvironments [36,37].
At the supramolecular level, many sustained release drug delivery systems (SRDDS) employ self-assembled nanostructures, such as micelles, vesicles, liposomes, or polymersomes, that can be destabilised or disassembled in response to particular stimuli. In systems based on lipids, changes in pH or temperature can alter the arrangement of the bilayer, leading to the release of the encapsulated drug. The incorporation of protonatable lipids (such as DOPE and CHEMS) can trigger a transformation from lamellar to hexagonal phases in acidic pH, causing destabilisation of the membrane. For polymeric micelles, external triggers (like redox reactions or exposure to light) can disrupt the crosslinks in the hydrophobic core or the linkers in the hydrophilic corona, which prompts the breakdown of unimers and the release of medications. Similarly, magnetic nanoparticles encased in liposomes can generate localised heat when exposed to alternating magnetic fields, causing the formation of temporary pores and facilitating drug release [38].
After the previous transformations are finalised, the subsequent phase involves the physical relocation of drug molecules into the external environment, primarily driven by diffusion and convection. The transport mechanism is represented by numerical values: 0.5 indicates Fickian diffusion, 1 signifies case-II transport (governed by erosion or relaxation), and values in between represent anomalous transport. Consequently, the kinetics of the overall release result from a combination of stimulus-induced structural modifications (swelling, cleavage, disruption) and mass-transfer mechanisms (diffusion, erosion, convection) [39].
The oral route remains the most user-friendly option for patients, but it encounters numerous biological obstacles: harsh gastric acidity, digestive enzymes, mucus barriers, fluctuating transit times, and first-pass metabolism. As a result, stimuli-responsive oral systems are designed to protect the drug in the stomach while enabling targeted release in the small intestine or colon through signals from pH, enzymes, or microbiota. Conventional design approaches utilise enteric or acid-sensitive coatings, pH-responsive hydrogels that expand at intestinal pH levels to release the medication, and enzyme-degradable linkers that are disrupted by colonic microbiota [40].
The main challenge in transdermal delivery is the stratum corneum. Stimuli-responsive transdermal systems, such as microneedle (MN) arrays, stimuli-sensitive dissolving polymers, and wearable patches, enable a less invasive method to overcome the outer skin barrier, providing on-demand or feedback-regulated drug administration. Strategies include glucose-responsive MNs for insulin delivery (employing enzyme or phenylboronic acid detection), temperature- or ROS-responsive coatings that dissolve in inflamed skin areas, and electrically activated patches for accurate dosing [41].
Implementing a drug delivery system for the eyes is recognised as a complex and challenging task due to the eye’s isolation as an organ, making drug administration quite difficult. Antibiotic eye drops are among the most commonly employed topical treatments for various ocular infections. Nonetheless, conventional ophthalmic formulations require frequent application to sustain an effective concentration at the infection site, as the rapid turnover of tears and significant drug elimination via nasolacrimal drainage result in low bioavailability of eye drops. The process of delivering medication to the eye faces challenges like tear replacement, blinking, barriers posed by the cornea and sclera, and restricted access to the posterior segment as a result of the blood-retinal barrier. Stimuli-responsive ocular systems aim to extend the duration the drug remains in the precorneal area (such as thermo- or ion-triggered in situ gels) or to initiate localised drug release within deeper tissues using techniques such as light-responsive nanoparticles, ultrasound-assisted strategies, or enzyme-degradable delivery systems [42].
The nasal route for administration offers a rapid and, in certain instances, a direct means to transport substances from the nose to the brain via the olfactory and trigeminal nerve pathways, making it an attractive option for Central Nervous System (CNS) therapies. The main obstacles include mucociliary clearance and a limited duration of presence. Formulations that are responsive to stimuli in the nasal region often include thermo- or ion-sensitive in-situ gels that solidify upon contact with nasal mucus or nanoparticles that respond to reactive oxygen species/enzymes that are tailored to exploit specific oxidative/inflammatory conditions for targeted release [43].
The lungs possess a large surface area and a thin epithelial layer, making them suitable for rapid systemic absorption and focused treatment of respiratory issues. However, successful inhalation requires controlling the size of particles, ensuring stability during aerosol creation, and preventing clearance by macrophages. Inhalable carriers that are responsive to particular lung conditions (such as elevated ROS in inflamed regions) or that react to external triggers (like magnetic guidance) are currently under development [44].
CONCLUSION
A major step towards individualised, accurate, and flexible therapeutic interventions is the development of stimuli-responsive drug delivery systems. SRDDS offer spatially and temporally controlled drug release that is not possible with traditional formulations by utilising the biochemical and biophysical properties of diseased tissues or by incorporating externally controlled triggers. Targeted delivery within complex microenvironments, especially in cancer and inflammatory disorders, is made possible by the wide variety of endogenous stimuli, including pH gradients, enzyme overexpression, redox imbalances, and temperature variations. In a similar vein, exogenous triggers- such as light, magnetic fields, ultrasound, and electrical stimulation, offer extra levels of control that improve treatment efficacy and safety. The development of carriers that experience swelling, contraction, phase transitions, or selective bond cleavage has been made possible by developments in polymer science, both natural and synthetic. These mechanisms underpin the high responsiveness and specificity observed in next-generation systems. Drug delivery systems that respond to stimuli are a big step towards individualised, accurate, and flexible therapeutic interventions. SRDDS offer spatially and temporally regulated drug release that is not possible with conventional formulations by utilising the biochemical and biophysical properties of diseased tissues or by incorporating externally controlled triggers. Targeted delivery within complex microenvironments is made possible by the wide variety of endogenous stimuli, including pH gradients, enzyme overexpression, redox imbalances, and temperature variations, especially in cancer and inflammatory disorders. Similar to this, exogenous triggers such as light, magnetic fields, ultrasound, and electrical stimulation, offer extra levels of control that improve treatment efficacy and safety. This development has been largely attributed to advances in polymer science, which have made it possible to design carriers that experience phase transitions, swelling, contraction, or selective bond cleavage.
CONFLICT OF INTEREST:
The authors declare that they have no conflict of interest.
REFERENCE
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10.5281/zenodo.17980253
