Stimuli-responsive polymeric micelles represent a sophisticated class of nanostructures designed to release their payload in response to specific environmental triggers. These systems leverage the unique physicochemical properties of amphiphilic block copolymers, which self-assemble into core-shell structures in aqueous solutions. The hydrophobic core serves as a reservoir for therapeutic agents, while the hydrophilic shell ensures colloidal stability. The responsiveness of these micelles to stimuli such as pH, temperature, redox potential, or enzymatic activity enables precise spatiotemporal control over drug release, making them highly attractive for targeted delivery applications.

pH-sensitive polymeric micelles exploit the variations in pH between physiological (7.4) and pathological environments, such as tumor tissues (6.5–7.0) or endolysosomal compartments (4.5–6.0). The responsiveness is achieved through the incorporation of ionizable groups that undergo protonation or deprotonation, altering the micelle's stability. Common pH-sensitive moieties include carboxyl groups (e.g., poly(acrylic acid)) and amine groups (e.g., poly(2-diethylaminoethyl methacrylate)). At physiological pH, these groups remain deprotonated or protonated, maintaining micelle integrity. However, in acidic environments, the protonation of carboxyl groups or deprotonation of amine groups disrupts the hydrophilic-hydrophobic balance, leading to micelle dissociation. Alternatively, acid-labile linkers such as hydrazone or acetal bonds can be used to tether drugs to the polymer backbone. Acidic conditions cleave these linkers, releasing the payload. For example, poly(ethylene glycol)-b-poly(aspartic acid) micelles with hydrazone-linked doxorubicin exhibit rapid drug release at pH 5.0 but remain stable at pH 7.4.

Thermoresponsive micelles rely on polymers with lower critical solution temperatures (LCST) or upper critical solution temperatures (UCST). Poly(N-isopropylacrylamide) (PNIPAM) is the most widely studied thermoresponsive polymer, with an LCST of approximately 32°C. Below the LCST, PNIPAM is hydrophilic and hydrated, while above it, the polymer collapses into a hydrophobic state. This transition can destabilize micelles, triggering drug release. Block copolymers like PNIPAM-b-poly(lactic acid) form micelles that disassemble when heated above the LCST, releasing encapsulated drugs. Other thermoresponsive polymers include poly(oligo(ethylene glycol) methacrylate) and poly(2-oxazoline)s, which offer tunable LCSTs by adjusting copolymer composition. For instance, increasing the hydrophobic content in poly(2-ethyl-2-oxazoline)-b-poly(ε-caprolactone) raises the LCST, enabling customization for specific applications.

Redox-responsive micelles capitalize on the significant difference in glutathione (GSH) concentrations between the extracellular (2–20 μM) and intracellular (2–10 mM) environments. Disulfide bonds, which are stable under oxidative conditions but cleave under reductive conditions, are commonly incorporated into the micelle design. For example, poly(ethylene glycol)-b-poly(ε-caprolactone) with disulfide linkages between blocks remains stable in circulation but dissociates upon intracellular GSH exposure, releasing the drug. Similarly, micelles with disulfide-crosslinked cores exhibit enhanced stability during systemic circulation but rapidly degrade in reducing environments. Another strategy involves using thiol-responsive linkers, such as thioketals, which cleave in response to reactive oxygen species (ROS) overexpressed in inflammatory or cancerous tissues.

Enzyme-responsive micelles are designed to release drugs in the presence of specific enzymes overexpressed in disease sites. These systems incorporate enzyme-cleavable substrates into the polymer backbone, shell, or core. For instance, matrix metalloproteinase-2 (MMP-2), which is upregulated in tumors, can cleave peptide sequences like GPLGIAGQ. Micelles with MMP-2-sensitive PEG shells shed their hydrophilic corona upon enzyme exposure, destabilizing the micelle and releasing the drug. Similarly, esterase-sensitive micelles use poly(ε-caprolactone) or poly(lactic acid) cores, which degrade via esterase-mediated hydrolysis in cells. Another approach involves phosphatase-sensitive micelles, where phosphate groups are removed by alkaline phosphatase, altering the polymer's solubility and triggering disassembly.

Material selection is critical for optimizing stimuli-responsive micelles. For pH-sensitive systems, poly(β-amino ester)s and poly(histidine) are popular due to their sharp pH-dependent transitions. Thermoresponsive micelles often employ PNIPAM or its copolymers, while redox-sensitive designs favor disulfide-containing polymers like poly(disulfide acrylate). Enzyme-responsive micelles utilize natural or synthetic peptides tailored to specific enzymes. The choice of hydrophobic block (e.g., poly(lactic-co-glycolic acid), poly(ε-caprolactone)) influences drug loading and release kinetics, while the hydrophilic block (e.g., PEG, poly(2-methyl-2-oxazoline)) governs stealth properties and circulation time.

Design strategies focus on balancing stability and responsiveness. Core-crosslinking enhances micelle stability but requires stimuli-labile crosslinkers for triggered release. Shell-shedding systems use cleavable PEG chains to expose hydrophobic cores, promoting cellular uptake. Hybrid designs combine multiple stimuli-responsive elements, such as pH- and redox-sensitive groups, to achieve sequential or synergistic release. For example, a micelle with pH-sensitive core-forming blocks and redox-sensitive crosslinks can first respond to tumor acidity, then intracellular GSH, ensuring precise drug delivery.

The mechanisms of drug release vary with the stimulus. pH-sensitive micelles rely on protonation-induced swelling or linker cleavage, while thermoresponsive systems depend on polymer collapse. Redox-sensitive micelles undergo disulfide reduction, and enzyme-responsive ones experience substrate cleavage. Each mechanism impacts release kinetics: pH- and enzyme-triggered release is typically rapid, whereas thermoresponsive release is more gradual. The release profile can be fine-tuned by adjusting polymer composition, linker chemistry, or crosslinking density.

Challenges remain in optimizing these systems for clinical translation. Stability in blood, controlled responsiveness, and scalable fabrication are key considerations. Advances in polymer chemistry and nanotechnology continue to refine stimuli-responsive micelles, enhancing their potential for precision medicine. By leveraging the unique properties of these materials, researchers can develop next-generation nanocarriers capable of delivering therapeutics with unprecedented spatial and temporal control.