Table 2.

Important class of cleavable systems utilizing cleavable conjugations for targeted cargo delivery

	Cleavable systems	Characteristics	Cargo loading and releasing strategy
Polymer/Hydrogel		• Different material such as dendrimer, polymersome, nanoemulsion, nanoaggregate and hydrogel can be synthesized by different methodologies. • Useful for delivery of hydrophobic and hydrophilic payloads. • Size, composition, stability, responsiveness and surface charge, together with loading efficacy and release kinetics can be precisely controlled. • Highly biocompatible and water soluble/dispersible with known in vivo clearance mechanism	• Payload is usually linked to backbone via stimuli-responsive covalent linkage which can be cleaved in diseased microenvironment, giving active agent.
Rigid Nanoparticles		• Can be precisely formulated into various sizes, shapes, and geometries. • Such systems have qualified for applications such as diagnostics, imaging and photothermal therapies. • They have high drug loading efficiency. • Nanostructures are highly stable and not concentration dependent. • Have a very low polydispersity index. • They can hold small drug molecules to large polymers and even relatively large antibodies.	• Their hollow counterpart can be detached/cleaved in the physiochemical conditions thereby releasing the cargo. • Cargo can be attached to the surface or loaded in the interior or surface. Physically loaded cargo is protected from the outer environment through attached surface coating or gatekeeper molecules.
Lipid Nanoparticles		• Lipid-based NPs can be easily modulated to control their physicochemical characteristics. That’s why these are the most common classes of FDA-approved nanomedicines. • Easily transformed into different nano-assemblies such as micelles, liposomes, cylindrical micelles, and sheets by the interplay of hydrophilic and hydrophobic units. • They are truly biomimetic and are highly compatible with biological systems. • Suitable for hydrophobic payloads.	• Most of such systems self- assemble under specific conditions while wrapping the cargo inside. Under the physiochemical changes of the diseased organ, intermediate linker cleaves to release the cargo.
Pro-Drug		• Mainly contains three components: cytotoxic agent, targeting moiety and chemical linker, and in some cases fluorescent probe. Cleavable linkers play a key role in the success of antibody-drug conjugates and targeting prodrugs. • Highly specific to diseased tissue. • Usually stable in blood circulation.	• Cargo is attached through covalent linkage. In these systems, inherent properties of physiological conditions are utilized to selectively release cytotoxins.

Cargo is either attached covalently to carrier scaffold through cleavable linker or loaded non-covalently.