Carrier-linked prodrugs represent a specialized class of prodrugs in which the active drug is covalently attached to a carrier molecule. These carriers are often designed to have a strong affinity for specific biological targets, enabling the prodrug to bypass biological barriers, such as cell membranes, or to home in on diseased tissues, like tumors. The carrier temporarily masks or alters the parent drug’s physicochemical properties, thereby improving solubility, stability, or pharmacokinetics. Once the prodrug reaches its intended site, the linkage between the carrier and the active drug is cleaved—typically via enzymatic or chemical hydrolysis—releasing the active compound and, depending on the system, either an inert or biologically active carrier moiety [7] .

An ideal carrier-associated prodrug fulfills several requirements. The prodrug should be less active or inactive in relation to the parent drug to be transported safely. The breakage of the linkage at the target site should be rapid and selective, yielding therapeutic levels of the active drug while minimizing alternative metabolic pathways and avoiding toxicity due to the carrier [7] . Carrier moieties are sometimes lipophilic in nature, such as PEG, fatty chains, macromolecules (albumin, antibody), which increase membrane permeabilization and drug stability.

The successes of carrier-linked prodrugs reflect the capabilities for strategic improvements with molecular transformation. One such example is Protaxel, which is a water-soluble carbonate conjugate of paclitaxel that follows pH-dependent intramolecular cyclization for the liberation of the active drug molecule, resulting in enhanced aqueous solubility and in vivo antitumor activity . Buparvaquone derivatives are another example, where derivatization with a phosphate moiety enhances aqueous solubility and skin permeation, making them promising candidates for the treatment of cutaneous leishmaniasis. In this case, the phosphate group does not act as a carrier but rather functions to improve the compound’s physicochemical properties. Furthermore, the ProTide technology also illustrates the value of carrier-linked design, in the sense that it delivers nucleoside monophosphates into cells and negates the constraining rate-limiting phosphorylation steps, while enhancing antiviral potency to a remarkable degree, seen in drugs such as Sofosbuvir for hepatitis C .

This novel concept is developing as it adapts through polymer chemistry, nanotechnology, and enzymatic activation to improve drug delivery and therapeutic effects in various clinical applications.

Bio-precursor prodrugs are a unique class of prodrugs that are internally converted into active drug molecules by metabolic mechanisms. Unlike carrier-linker prodrugs, bio-precursor prodrugs have no carrier part. Thus, the drug is instead chemically modified into an inactive biochemical precursor of the drug, which is converted to the active drug in a biological system [7] [8] . This method can be especially useful for regulating the lipophilicity, stability, and organotropism of a pharmakon.

The bio-precursor prodrug is generally activated by enzymatic reactions such as oxidation, reduction, or hydrolysis. For example, Sulindac is a bio-precursor of its active sulfide metabolite, and reductive activation by gut bacteria leads to less gastric irritation than observed with the traditional NSAIDs . Tegafur is an orally administered N-tetrahydrofuran derivative of 5-fluorouracil (5-FU), a fluoropyrimidine. It is converted to 5-FU primarily by cytochrome P450 enzymes, enabling tumor-selective activation and thereby reducing systemic toxicity during cancer chemotherapy [7] . Likewise, Valacyclovir, a prodrug of acyclovir, improves oral bioavailability by being hydrolyzed by esterase of the intestinal mucosa; therefore, it is more favored for antiviral therapy .

A bio-precursor prodrug is especially useful in overcoming certain pharmacokinetic and pharmacodynamic issues. Their main advantage is improved bioavailability, due to avoidance of first-pass metabolism or low absorption, leading to increased plasma levels of the active substance. Furthermore, bio-precursor prodrugs play a role in reduced toxicity as they allow for tissue-specific activation, thus reducing side effects—e.g., sulindac and tegafur [8] . The second benefit is increased stability: as it can protect the active drug from degradation and further decomposition prior to storage or after release into the body, maintaining the pharmacological activity [7] .

The development of prodrug bio-precursors also evolves further with the integration of computational modeling and enzyme engineering for accurate prediction and selection of activation pathways. Therefore, bio-precursor prodrugs will continue to be relied on as an important method in future drug design, as promising concepts to address and solve established problems in pharmacokinetics, targeting therapeutic benefit profiles, as we are able to claim here.

Self-immolative prodrugs are another class of prodrugs that are good for controlled drug release. This type of prodrug uses an unusual mechanism: it triggers a cascade of reactions, ultimately leading to the release of the active drug. The concept was first introduced in 1981 by Katzenellenbogen et al.. His team demonstrated the utility of 1,4- and 1,6-benzyl elimination as a mechanism for controlled drug release [9] .

The general design of self-immolative prodrugs includes three key components:

1) A trigger unit, which responds to specific stimuli such as enzymatic activity, redox conditions, or light.

2) A self-immolative spacer, which undergoes an elimination reaction after activation of the trigger.

3) An active drug payload, released after the spacer decomposes [10] .

The flexibility of self-immolative prodrugs relies on the possibility of responding to diverse bio-stimuli, which allows for regulated and localized drug release. For instance, hydrogen peroxide responsive systems exploit the oxidative stress of certain pathological states, such as cancerous tissues, to release a therapeutic with specificity. BDP-NAC is one such case employing an aryl boronic acid pinacol ester trigger to release persulfides with cytoprotective activity that quenches reactive oxygen species (ROS) . Enzyme-activated prodrugs, such as esterase-triggered prodrugs, were developed for cancer therapy that can release anticancer reagents such as carbonyl sulfide (COS) or hydrogen sulfide (H₂S), both with favorable pharmacological effects . Moreover, light-activated systems use photocaged thiocarbamates to precisely release COS or H₂S in space and time, allowing for an extremely localized treatment with reduced ability to reach systemic circulation .

Self-immolative prodrugs hold some promise for therapeutically selective drug activation for several reasons; perhaps most noteworthy is their ability to generate multiple products from the same triggering event, a characteristic that has been exploited in signal amplification and drug delivery strategies [9] . This method is particularly useful in the release of sulfur-containing compounds such as persulfides that participate in important redox-signaling cascades and cellular protection.

Recent progress in self-immolative prodrug design has aimed at improving trigger specificity and release kinetics. Modular systems, such as BDP-Fluor, have presented selective H₂O₂-triggered activation, showing great therapeutic promise for oxidative stress-related diseases, such as myocardial infarction and neurodegenerative diseases [10] .

Being a promising approach, self-immolative prodrugs will be used more widely in oncology, inflammation, and precision medicine as a potential modality to resolve the drawbacks associated with traditional drug delivery systems.

Prodrugs can be generally divided into two types according to the position where they are converted to the drug (Type I and Type II). It provides a perspective on the pharmacokinetics, efficacy, and safety of prodrugs by the consideration of the biological environment in which the activation is done . The prodrugs of type I are activated intracellularly, on the target therapeutic, and/or in the main organ of first pass. In subtype IA, the prodrug(s) are converted to their active metabolites inside the cell, where the therapeutic effect is produced, e.g., 5-fluorouracil and zidovudine. This direct activity on the therapeutic site is responsible for high efficacy and reduced side effects. Type IB prodrugs, such as sulindac or heroin, in contrast, are activated in a metabolic tissue, such as the liver, gastrointestinal mucosa, or lungs. For example, sulindac is metabolized to an active sulfide metabolite in the liver; thus, it causes less gastrointestinal irritation compared with other NSAIDs. Heroin also undergoes enzymatic hydrolysis in hepatic tissues to morphine, which produces its analgesic effect as well .

In contrast, type II prodrugs are bio-reversible prodrugs, which are activated outside biological fluids at or near the site of therapeutic targets. They are also divided into three subtypes. Prodrugs of type IIA, such as sulfasalazine, undergo conversion in the GI fluids. Sulfasalazine is metabolized by colonic bacteria to sulfate pyridine and mesalamine, which both exert their therapeutic effect locally in the colon, thus being useful in the treatment of inflammatory bowel diseases. Type IIB prodrugs, such as fosphenytoin, are hydrolyzed in the systemic circulation or extracellular fluid to achieve fast activation and enhanced solubility. Type IIC prodrugs have been developed for activation in close proximity to target cells or tissues, which commonly require a specific enzymatic action. One of the most notable examples is ADEPT (antibody-directed enzyme prodrug therapy), in which a prodrug is activated at the tumor location when in the conjugated enzyme-antibody complex, while the systemic toxicity can be reduced [11] .

Between the two classes, type I prodrugs are particularly dependent on the intracellular metabolism to activate with desirable tissue-specific therapeutic effects, as observed with antiviral nucleosides and lipid-lowering statins. In comparison, Type II prodrugs take advantage of the extracellular space or systemic enzyme activity for activation, which can be especially useful for diseases where the desired drug effect occurs in non-cellular specific or systemic compartments, such as GI and circulatory diseases. Some prodrugs represent a mixed nature of both types, so-called Mixed-Type prodrugs. These compounds are activated at several levels simultaneously or in a step-wise manner. For example, the Sequential Mixed-Type prodrug tenofovir disoproxil fumarate is activated in the gastrointestinal fluids (Type IIA) and in the target cell (Type IA). This double-targeting strategy can achieve effective in vivo delivery and therapeutic performance and bypass the PK barriers [11] .

The Type I and Type II classification can define a rational framework to gain insights into the mechanism of action of prodrugs, underlining different approaches to drug design. Type I prodrugs are superior in cellular targeting, whereas Type II prodrugs are suitable for systemic and extracellular applications. A combination of these categories can further enable precision medicine and targeted therapeutics delivery.

Therapeutic plasma concentration is hard to achieve when drugs have poor aqueous solubility. Thus, prodrugs that can increase bioavailability by adding hydrophilic or lipophilic functional groups are very favorable. For example, fosamprenavir, a prodrug of the HIV protease inhibitor amprenavir, increases water solubility and facilitates better oral absorption. After absorption, it is directly converted into Amprenavir by cellular phosphatases, thereby enhancing oral absorption and bioavailability compared to direct administration of Amprenavir [12] .

Another example is Valacyclovir, a prodrug of Acyclovir. Acyclovir has limited bioavailability (15% - 30%) due to poor absorption in the gastrointestinal tract. Valacyclovir, an L-valyl ester prodrug of Acyclovir, significantly improves its bioavailability (approximately 55%) by enhancing intestinal absorption via peptide transporters. Once in circulation, it is hydrolyzed to release Acyclovir, providing better antiviral efficacy with lower dosing frequency [1] .

Curcumin, a natural compound with extensive pharmacological benefits, suffers from poor bioavailability due to low solubility and rapid metabolism. To address this, curcumin prodrugs have been developed, incorporating promoieties that enhance stability and absorption. Studies indicate that curcumin prodrugs improve systemic circulation levels and prolong curcumin’s therapeutic effects [13] .

Certain drugs degrade rapidly in the stomach due to acidic conditions or enzymatic metabolism. Prodrug modifications, such as esterification or phosphate conjugation, protect the active drug from premature degradation. Omeprazole, a proton pump inhibitor, is a classic example where the prodrug formulation allows it to remain stable until activation in the parietal cells [7] .

Another example is the development of amino acid prodrugs, which improve stability through strategic linker modifications. Research indicates that prodrugs containing methoxy, ethoxy, and propylene glycol linkers exhibit varying degrees of stability, with propylene glycol-linked prodrugs showing the highest stability at physiological pH [14] . The study further highlights that amino acid side chains influence stability, with aliphatic amino acid-based prodrugs being more stable than their aromatic counterparts.

Ester prodrugs also play a crucial role in improving drug stability by modifying ester linkages. For example, lipid ester prodrugs utilize fatty acid moieties to protect the drug from premature hydrolysis and enhance membrane permeability [15] . Modifications like this can help drugs to resist rapid degradation in the gastrointestinal tract, ensuring that the drug is optimally absorbed.

Some prodrug design strategies include using tissue-specific enzymes, pH variation, and metabolic pathways. By doing so, site-specific activation can be achieved. In oncology, the goal is to selectively release cytotoxic agents in tumor cells while minimizing systemic toxicity. For instance, capecitabine is a prodrug of 5-fluorouracil that undergoes enzymatic conversion primarily in tumor tissues, reducing off-target effects [1] .

Another approach to targeted delivery involves esterase-sensitive prodrugs, which activate in specific tissues where esterase enzymes are overexpressed. For example, esterase-responsive nanoparticles have been utilized to selectively release anticancer drugs in tumor environments, thereby improving treatment efficacy and reducing systemic toxicity [15] .

Similarly, pH-sensitive prodrugs leverage the acidic microenvironment of tumors to trigger drug activation. Doxorubicin-based prodrugs incorporating acid-labile linkers have demonstrated improved tumor selectivity, reducing adverse effects on normal tissues [14] .

By controlling the release and distribution of active drugs, prodrugs help minimize adverse effects. In NSAIDs, direct administration can lead to gastrointestinal irritation, but prodrug forms such as nabumetone bypass the gastric mucosa and are activated in the liver, reducing gastric toxicity [8] .

Another strategy involves enzyme-specific prodrugs, which are activated only in target tissues, thereby limiting systemic exposure and reducing side effects. For example, phosphate-based prodrugs have been used to reduce renal toxicity in antiviral therapies by ensuring drug activation only after absorption [15] .

Moreover, site-specific hydrolysable prodrugs have been engineered to remain stable during circulation but undergo enzymatic conversion at the intended site of action. This approach has been particularly effective in reducing hepatotoxicity in chemotherapeutic agents by confining drug activation to tumor tissues [14] .

Carrier-linked prodrugs are designed by attaching promoieties in the form of a dashboard via a covalent bond, so that undesirable properties, such as poor solubility or a short half-life, can be mitigated. The carrier is cleaved with the help of enzymes or by chemical means to release the active drug. Enalapril is an example of a carrier-linked drug. It is converted to enalaprilat (the active form) through hydrolysis in the liver by enzymes such as carboxylesterase [16] .

The design for a carrier-linked prodrug consists of carefully selecting the promoieties. It must be both non-toxic and able to be split enzymatically or chemically by physiological conditions [7] . Commonly available carrier moieties, such as PEG (polyethylene glycol), fatty acid chains, and macromolecules like albumin or antibodies, can enhance bioavailability in addition to allowing for tissue-specific targeting [13] .

This is illustrated by a few examples of advanced strategies for prodrug development, which show how different approaches can be used to improve drug efficacy and delivery.

An example is the prodrug of Oseltamivir carboxylate, Oseltamivir, which improves oral availability by means of esterification and covers up polar groups. Also, paclitaxel prodrugs like Protaxel use carbonate linkages with pH-dependent cleavage, enhancing both solubility and tumor specificity; thus, they offer a more successful means for treating cancer.

For a successful application, the linker between the drug and carrier must demonstrate:

1) Sufficient stability during formulation and circulation,

2) Rapid and site-specific cleavage in the body,

3) Inertness of the released carrier moiety,

4) Improved pharmacokinetics or therapeutic index over the parent drug alone [7] .

Overall, carrier-linked prodrugs represent a rational and versatile approach to overcoming the limitations of many lead drug candidates and are a cornerstone in modern prodrug design.

Mutual prodrugs are a specialized subgroup of carrier-linker prodrugs in which the carrier is not an inert molecule, but rather another pharmacologically active drug. This design consists of two active drugs linked to one another by covalent bonds. Each drug functions as a prodrug for the other, so that both drugs will be released whenever there is enzymatic or chemical cleavage. This dual-drug approach can enhance therapeutic outcome by delivering drugs with synergistic effects or complementary actions while minimizing side reactions [17] .

The mutual prodrug strategy can be especially helpful when one drug plays the role of an adjuvant in targeting or delivering the other, or when both drugs face similar challenges concerning bioavailability and/or toxicity. This approach is also highly advantageous if combination therapy is desired, as it allows two pharmacologically active agents to be combined into a single molecular entity, thereby offering streamlined administration and the potential for enhanced therapeutic synergy.

Mutual prodrug Aspacardin is an example. Aspirin and paracetamol are chemically linked into a single molecule in this case. In this form, it exhibits enhanced gastrointestinal tolerability and improved synergistic analgesic activity. Likewise, sultamicillin is a mutual prodrug combining ampicillin and sulbactam. This combination is designed to overcome β-lactamase-mediated resistance while enhancing oral bioavailability [17] .

Overall, mutual prodrugs extend the utility of carrier-linked strategies by incorporating bioactive synergy, targeting potential, and co-delivery benefits, making them a powerful tool in rational prodrug design.

Co-drugs are structurally like mutual prodrugs but often do not require complete cleavage into separate active agents. Instead, they function as a single hybrid molecule where pharmacological effects or improved pharmacokinetics are achieved through combination. Co-drugs are frequently used to overcome poor absorption or short half-lives [1] .

The terms co-drug and mutual prodrug are often used interchangeably in the field of prodrug design, as both involve the covalent linkage of two pharmacologically active agents into a single molecular entity. Upon administration, the co-drug or mutual prodrug is inactive but is designed to release both active components through enzymatic or chemical cleavage in vivo. However, subtle distinctions exist in their conceptual application. Mutual prodrugs are traditionally defined as bio-reversible conjugates where each drug acts as promoieties for the other, typically linked via a cleavable bond such as an ester or amide. These are often designed with site-specific release in mind, sometimes to reduce toxicity or improve absorption. In contrast, the term co-drug is broader and may refer to dual-drug conjugates with or without a cleavable spacer, often emphasizing synergistic therapeutic effects or pharmacokinetic enhancements. Despite these nuances, in most contemporary pharmaceutical contexts, the two terms are functionally equivalent and used interchangeably [18] .

Bio-precursor prodrugs are inactive molecules that undergo molecular modification within the body to regenerate the active drug without requiring a distinct carrier moiety. Unlike carrier-linked prodrugs, bio-precursors are derived through structural alteration of the parent drug itself, typically via redox reactions, hydrolysis, or enzymatic cleavage [6] [15] .

Bio-precursor prodrugs do not require an additional carrier but undergo metabolic transformation into an active form. These transformations often involve oxidation, reduction, or hydrolysis. Levodopa, a prodrug of dopamine, crosses the blood-brain barrier and is converted enzymatically to dopamine in the CNS, overcoming the poor penetration of direct dopamine administration [1] . The main goal of bio-precursor prodrug design is to overcome challenges such as poor oral bioavailability, rapid metabolism, or selectivity by enabling targeted in vivo activation. This approach is particularly useful for drugs that are otherwise unstable or poorly absorbed in their active form [19] .

Sulindac is an example of a bio-precursor prodrug. It is a non-steroidal anti-inflammatory drug. The active sulfide form of the drug is converted through reductive metabolism in the liver. By doing so, the side effects in the gastrointestinal tract are reduced [19] . Another example is Tegafur, which is an oral anticancer agent. It is metabolized by the liver into 5-fluorouracil (5-FU). Tegafur is used as a prodrug instead of 5-FU because it allows for oral administration and provides a slower, more controlled release of the active drug. This helps improve effectiveness and reduce the severe side effects associated with direct 5-FU treatment [15] .

This approach prevents the use of bulky and potentially toxic promoieties, but also allows a simpler chemical structure for the prodrug itself. However, their reliance on metabolic enzymes introduces variability based on interindividual differences, which may affect the consistency of drug activation across patient populations [19] .

Beyond carrier-linked and bio-precursor prodrugs, several advanced strategies have been developed to enhance site-selectivity, stability, and therapeutic synergy. These include double prodrugs, mutual prodrugs, targeted prodrugs, macromolecular prodrugs, self-immolative systems, and co-drugs [1] [6] [19] .

Double prodrug strategy, also referred to as cascade latentiation, involves the design of a prodrug that itself is a derivative of another prodrug. In this sequentially activated system, the initial pro-prodrug undergoes an enzymatic or chemical transformation to form an intermediate prodrug, which is subsequently converted to the active parent drug. This approach provides enhanced control over drug release, improved stability, and potential for site-specific activation [20] .

This concept is particularly useful when single prodrugs suffer from poor chemical stability or incomplete activation. For instance, a chemically labile prodrug can be stabilized through further derivatization into a double prodrug form, where the first cleavage step is enzymatic, thus offering better in vitro formulation properties (e.g., longer shelf life), while ensuring efficient in vivo activation [20] .

The double prodrug strategy offers a powerful means of optimizing drug delivery, particularly in cases where conventional prodrugs are limited by instability or poor pharmacokinetics.

A classic example is 6-deoxyacyclovir, a double prodrug of the antiviral agent acyclovir. While acyclovir suffers from poor oral bioavailability due to low solubility, 6-deoxyacyclovir is significantly more water-soluble and undergoes in vivo conversion by xanthine oxidase to release acyclovir, improving absorption from 15 - 20% to over 75% [20] .

In ophthalmology, pilocarpine diesters represent another successful application. Although pilocarpine acid monoesters improved corneal penetration, they were chemically unstable in solution. The development of a double ester (diester) prodrug provided enhanced aqueous stability and a two-step activation mechanism: enzymatic hydrolysis followed by intramolecular lactonization, resulting in improved shelf life and ocular bioavailability [20] .

This strategy is especially valuable for improving prodrug stability during storage and formulation, enabling site-specific drug delivery through transport enhancement and localized activation, extending drug release profiles for compounds with short half-lives, and modulating physicochemical properties such as solubility or lipophilicity via layered promoieties design. Its versatility has been demonstrated across various drug classes, including antivirals, benzodiazepines, and antiglaucoma agents, making it a rational and robust solution when traditional prodrug approaches prove insufficient.

Targeted prodrugs are designed for selective activation at specific biological sites such as tumors, inflamed tissues, or organs with unique enzyme expression. This can be achieved through:

Enzyme-sensitive prodrugs are designed to be activated by specific enzymes that are overexpressed or uniquely present in diseased tissues. This approach enables site-specific drug release, thereby enhancing therapeutic efficacy while reducing systemic toxicity. For instance, enzymes such as β-glucuronidase, which are overexpressed in tumor microenvironments, have been used to trigger the release of anticancer agents from glucuronide-linked prodrugs. Similarly, protease-sensitive linkers have been incorporated in prodrugs to target matrix metalloproteinases (MMPs), which are commonly elevated in cancer and inflammatory conditions. Advanced therapeutic systems like Antibody-Directed Enzyme Prodrug Therapy (ADEPT) utilize engineered enzymes conjugated to antibodies that bind selectively to tumor cells. Once localized, the systemically administered prodrug is cleaved by the enzyme, ensuring localized drug activation. The specificity and catalytic efficiency of enzymes make this strategy a powerful tool for precision drug delivery.

pH-sensitive prodrugs exploit the distinct acidic environments of pathological tissues, such as tumors, sites of inflammation, or intracellular endosomes and lysosomes. These regions often exhibit lower pH values (around pH 6.5 or lower) compared to normal physiological pH (approximately 7.4). By incorporating acid-labile linkers—such as hydrazones, cisaconityl groups, or acetal bonds—into prodrug structures, drug release can be triggered specifically under acidic conditions. For example, doxorubicin has been conjugated via a hydrazone bond to polymeric carriers, resulting in pH-responsive systems that release the active drug in the acidic tumor milieu or within acidic intracellular compartments following endocytosis. This approach minimizes premature drug release in systemic circulation and enhances accumulation at the target site. The simplicity and environmental responsiveness of pH-sensitive designs make them highly attractive for developing safer and more effective therapies.

Redox-sensitive prodrugs are engineered to respond to the differences in redox potential between healthy and diseased tissues, particularly in cancer cells, which often exhibit elevated levels of intracellular reducing agents like glutathione (GSH). By incorporating redox-labile linkages—such as disulfide or thioketal bonds—into the prodrug structure, selective activation can be achieved within the reductive cytosol of tumor cells. Upon cellular uptake, the high intracellular GSH concentration cleaves the disulfide bonds, releasing the active drug. This strategy has been successfully applied in various anticancer systems, including nanoparticle-based drug conjugates and polymeric micelles. For example, paclitaxel prodrugs with disulfide linkers have demonstrated improved tumor targeting and reduced systemic toxicity. Redox-sensitive systems offer a dynamic and selective mechanism of drug release, particularly useful in targeting intracellular compartments or oxidative stress-related pathologies [1] [21] .

Macromolecular prodrugs use polymers, proteins, or antibodies as carriers covalently linked to the active drug. These systems can enhance pharmacokinetics, prolong circulation time, and facilitate passive or active targeting. PEGylated drugs (e.g., PEG-interferon) and polymer-drug conjugates are prominent examples used in cancer and antiviral therapies [19] .

Macromolecular prodrugs (MPs) have emerged as an attractive approach in drug delivery, where drugs are covalently linked to high-molecular-mass carriers, which can be synthetic polymers or endogenous proteins. Such macromolecular conjugates typically bear multiple copies of the drugs, resulting in improved pharmacokinetic properties, a prolonged blood half-life, and passive tumor accumulation through the enhanced permeability and retention (EPR) effect. Recent developments of MP designs are based on biodegradable main chain polymers, such as HPMA copolymers with cleavable GFLG linkers or reductive-sensitive backbones containing disulfide bonds. They enable triggered degradation and drug release in response to intracellular or tumor-associated stimuli, thereby decreasing nonspecific toxicity. Furthermore, albumin-polymer conjugates are considered an attractive alternative, leveraging the long half-life and receptor-mediated recycling of albumin to carry high amounts of drugs while retaining biocompatibility. These developments point out MP systems as a flexible and translationally appealing strategy for targeted, efficient, and safer drug delivery [22] .

Self-immolative prodrugs are an advanced construction principle for the controlled liberation of bioactive agents in a stimulus-triggered cascade reaction. At the core of the idea lies a cleavable “trigger” unit, directly attached to the warhead via a self-immolative spacer, in general, minimally comprising a 1,4- or 1,6-benzyl elimination motif, was postulated. When stimulated by a target environment (example: pH, enzymatic or reactive oxygen species), the trigger is extricated, and a spontaneous intramolecular reaction is activated, thus enabling the release of the drug. Dillon et al. exploited this feature to design persulfide-releasing prodrugs triggered only by oxidative stress. Their BDP-NAC system utilizes an aryl boronic ester, which reacts with H₂O₂, causing it to undergo self-immolation and release the NAC-SSH, a powerful antioxidant. Such precision, temporal, and spatial control of drug activation and minimization of off-target effects make self-immolative linkers a highly favorable method for stimulus-responsive drug delivery [10] .

Together, these approaches expand the landscape of prodrug design, offering more quantitative and precise control over drug release, targeting, and therapeutic synergy.