Stimuli-responsive dendrimers represent a sophisticated class of nanocarriers designed for controlled drug delivery, capable of releasing their payload in response to specific physiological or external triggers. These dendritic architectures offer precise spatial and temporal control over drug release, enhancing therapeutic efficacy while minimizing off-target effects. The responsiveness of these systems arises from strategic chemical modifications to the dendrimer structure, enabling sensitivity to pH, redox potential, enzymatic activity, or light. Each trigger exploits distinct biological or environmental conditions, allowing for site-specific delivery in complex physiological systems.

pH-sensitive dendrimers capitalize on the acidic microenvironments found in pathological tissues, such as tumors or inflammatory sites, as well as in intracellular compartments like endosomes and lysosomes. The chemical design typically incorporates ionizable groups that undergo protonation or structural changes at lower pH values. Common modifications include the integration of carboxylate, amine, or acetal groups into the dendrimer framework. For instance, poly(amidoamine) (PAMAM) dendrimers modified with pH-labile linkages, such as hydrazone or acetal bonds, between the drug and the dendritic scaffold ensure stability at physiological pH (7.4) but cleave in acidic conditions (pH 5.0–6.5). This selective bond cleavage facilitates drug release in tumor tissues, where the extracellular pH is often lower due to glycolytic activity. Additionally, pH-sensitive dendrimers can exploit the endosomal escape mechanism, where protonation of tertiary amines in the dendrimer structure induces a "proton sponge" effect, disrupting the endosomal membrane and promoting cytosolic delivery of therapeutic agents.

Redox-responsive dendrimers are engineered to release drugs in environments with elevated glutathione (GSH) levels, such as the intracellular cytoplasm or tumor tissues. The high redox potential gradient between the extracellular space (2–20 μM GSH) and the intracellular compartment (2–10 mM GSH) provides a reliable trigger for drug release. Disulfide bonds are the most widely employed redox-sensitive linkers due to their stability in circulation but rapid cleavage in reductive environments. Dendrimers functionalized with disulfide linkages between their core or branches and the drug payload ensure controlled release upon exposure to cytoplasmic GSH. For example, disulfide-crosslinked PAMAM dendrimers demonstrate minimal drug leakage in systemic circulation but undergo rapid degradation upon cellular internalization, releasing the encapsulated drug. This approach is particularly advantageous for delivering chemotherapeutic agents, as cancer cells often exhibit higher GSH concentrations than normal cells, enabling selective toxicity.

Enzyme-responsive dendrimers leverage the overexpression of specific enzymes in diseased tissues to achieve targeted drug release. These systems incorporate enzyme-cleavable substrates, such as peptide sequences or ester bonds, into the dendrimer structure. For instance, matrix metalloproteinases (MMPs), which are overexpressed in tumor microenvironments, can cleave peptide sequences like GPLGIAGQ, enabling site-specific drug release. Similarly, esterase-sensitive dendrimers exploit the high esterase activity in lysosomes, where ester bonds are hydrolyzed to release the drug payload. The specificity of enzyme-responsive systems minimizes off-target effects and enhances therapeutic precision. Dendrimers functionalized with cathepsin B-cleavable linkages have been explored for delivering anticancer drugs, as cathepsin B is frequently upregulated in malignant cells. The design of these dendrimers requires careful selection of enzyme substrates to ensure compatibility with the target tissue's enzymatic profile.

Light-responsive dendrimers offer spatiotemporal control over drug release through external irradiation, enabling on-demand delivery with high precision. These systems incorporate photolabile groups, such as o-nitrobenzyl esters or coumarin derivatives, which undergo cleavage upon exposure to specific wavelengths. Ultraviolet (UV) or near-infrared (NIR) light is commonly used, with NIR offering deeper tissue penetration and reduced phototoxicity. For example, dendrimers conjugated with o-nitrobenzyl-linked drugs remain stable in the absence of light but release the payload upon UV irradiation. NIR-responsive systems often employ two-photon absorption or upconversion mechanisms, where NIR light is converted to UV or visible light to trigger bond cleavage. Light-responsive dendrimers are particularly useful for treating localized conditions, such as solid tumors, where external light can be precisely applied to the target site. The ability to control the timing and location of drug release enhances therapeutic outcomes while reducing systemic exposure.

The applications of stimuli-responsive dendrimers span a wide range of therapeutic areas, with cancer therapy being the most prominent. Tumor-specific triggers, such as acidic pH, high GSH levels, or overexpressed enzymes, enable targeted delivery of chemotherapeutics, reducing side effects on healthy tissues. For example, pH-sensitive dendrimers loaded with doxorubicin have demonstrated enhanced antitumor efficacy in murine models, with significantly lower cardiotoxicity compared to free doxorubicin. Similarly, redox-responsive dendrimers delivering paclitaxel exhibit improved tumor accumulation and reduced systemic toxicity. Beyond oncology, these systems are explored for treating inflammatory diseases, where pH or enzyme triggers can target inflamed tissues. Neurodegenerative disorders also benefit from redox-responsive dendrimers, as oxidative stress is a hallmark of conditions like Alzheimer's disease.

In gene therapy, stimuli-responsive dendrimers facilitate the delivery of nucleic acids, such as siRNA or plasmid DNA, with controlled release in target cells. pH-sensitive dendrimers protect genetic material during systemic circulation but release it upon endosomal acidification, enhancing transfection efficiency. Redox-responsive systems ensure cytoplasmic delivery by exploiting the reductive environment, bypassing lysosomal degradation. These approaches address key challenges in gene delivery, including stability, cellular uptake, and intracellular trafficking.

The design of stimuli-responsive dendrimers requires careful consideration of biocompatibility, biodegradability, and pharmacokinetics. Polyester-based dendrimers, such as those derived from 2,2-bis(hydroxymethyl)propionic acid, offer biodegradability and low toxicity, making them suitable for clinical translation. PEGylation of dendrimers improves circulation time and reduces immunogenicity, while targeting ligands, such as folic acid or RGD peptides, enhance tissue specificity. The multifunctionality of dendrimers allows for the integration of imaging agents, enabling simultaneous diagnosis and therapy in theranostic applications.

Despite their promise, challenges remain in the clinical translation of stimuli-responsive dendrimers. Scalable synthesis, batch-to-batch consistency, and regulatory approval are critical hurdles. Additionally, the complexity of biological systems necessitates rigorous in vivo validation to ensure trigger specificity and therapeutic efficacy. Future research will focus on optimizing dendrimer architectures for multifunctional responsiveness, combining multiple triggers for enhanced precision. Advances in computational modeling and high-throughput screening will accelerate the design of next-generation stimuli-responsive dendrimers, paving the way for personalized nanomedicine.