Gelatin nanoparticles represent a promising class of biodegradable polymeric nanomaterials with tunable thermoresponsive properties, making them suitable for biomedical applications such as drug delivery and photothermal therapy. Their biocompatibility, biodegradability, and ease of functionalization have positioned them as a preferred choice for controlled release systems. A critical aspect of their utility lies in the ability to modulate their thermal response and degradation kinetics through crosslinking strategies and synthesis parameters.

**Synthesis via Desolvation Method**
The desolvation technique is widely employed for producing gelatin nanoparticles due to its simplicity and reproducibility. In this method, gelatin is dissolved in an aqueous solution under controlled temperature, typically between 40-50°C, to ensure complete solubilization. A desolvating agent, such as ethanol or acetone, is then added dropwise to induce the coacervation of gelatin molecules, leading to nanoparticle formation. The process is highly dependent on pH, with optimal nanoparticle formation occurring near the isoelectric point of gelatin (pH ~5-9).

Particle size can be controlled by adjusting parameters such as gelatin concentration, desolvating agent addition rate, and stirring speed. Studies have demonstrated that lower gelatin concentrations (1-5% w/v) yield smaller nanoparticles (50-200 nm), while higher concentrations result in larger aggregates. The addition of surfactants, such as Tween 80, can further stabilize the nanoparticles and prevent aggregation.

**Thermoresponsive Behavior and Gelation Modulation**
Gelatin exhibits a reversible sol-gel transition influenced by temperature, a property that can be fine-tuned for specific applications. The gelation temperature of gelatin nanoparticles depends on the degree of crosslinking and the molecular weight of the gelatin used. Type A gelatin (derived from acid hydrolysis) typically has a lower gelation point (~25-30°C) compared to Type B gelatin (alkaline hydrolysis, ~30-35°C).

Modifying the gelation temperature is crucial for applications requiring temperature-triggered drug release. Incorporating co-polymers or plasticizers can shift the transition temperature. For instance, blending gelatin with poly(N-isopropylacrylamide) (PNIPAM) can lower the gelation point to near-physiological temperatures, enabling controlled release in response to mild hyperthermia.

**Crosslinking Strategies for Controlled Degradation**
Crosslinking is essential to enhance the stability of gelatin nanoparticles in physiological conditions while controlling their degradation rate. Two widely used crosslinkers are glutaraldehyde and genipin, each offering distinct advantages.

Glutaraldehyde, a bifunctional crosslinker, reacts with the amino groups of lysine residues in gelatin, forming Schiff base linkages. While highly effective in stabilizing nanoparticles, its potential cytotoxicity necessitates careful optimization of crosslinking density. Studies indicate that glutaraldehyde concentrations between 0.1-1% (w/w of gelatin) provide sufficient stability without significant toxicity.

Genipin, a natural crosslinker derived from gardenia fruit extract, offers a biocompatible alternative. It forms blue-pigmented complexes upon reaction with gelatin, allowing visual confirmation of crosslinking. Genipin-crosslinked nanoparticles exhibit slower degradation rates compared to glutaraldehyde-crosslinked ones, making them suitable for sustained drug delivery. The crosslinking efficiency of genipin is typically lower, requiring higher concentrations (2-5% w/w) to achieve comparable stability.

Other crosslinking methods include enzymatic approaches using transglutaminase or physical crosslinking via UV irradiation. Enzymatic crosslinking provides high specificity but may increase production costs, while UV crosslinking is rapid but requires photoactive modifications to gelatin.

**Applications in Photothermal Therapy**
The thermoresponsive nature of gelatin nanoparticles makes them ideal for photothermal therapy (PTT), where localized heating is used to ablate tumor cells. By incorporating photothermal agents such as gold nanorods or indocyanine green (ICG), gelatin nanoparticles can convert near-infrared (NIR) light into heat, triggering drug release and inducing hyperthermia.

Crosslinked gelatin nanoparticles loaded with ICG have demonstrated efficient heat generation under NIR irradiation, with temperature increases of 10-15°C observed within minutes. The controlled degradation of crosslinked nanoparticles ensures sustained release of therapeutic agents while maintaining structural integrity during heating cycles.

**Degradation Kinetics and Drug Release Profiles**
The degradation rate of gelatin nanoparticles is influenced by crosslinking density and environmental factors such as pH and enzymatic activity. In vitro studies show that glutaraldehyde-crosslinked nanoparticles degrade over 7-14 days in physiological conditions, whereas genipin-crosslinked particles may persist for up to 21 days.

Drug release profiles correlate with degradation kinetics, with burst release observed in loosely crosslinked systems and sustained release in densely crosslinked nanoparticles. For temperature-sensitive applications, the release can be further modulated by external heating, enabling on-demand delivery.

**Conclusion**
Gelatin nanoparticles offer a versatile platform for thermoresponsive drug delivery and photothermal therapy, with their properties finely adjustable through synthesis and crosslinking strategies. The desolvation method provides a robust route for nanoparticle fabrication, while crosslinkers like glutaraldehyde and genipin enable precise control over stability and degradation. Their biocompatibility and responsiveness to external stimuli make them promising candidates for next-generation therapeutic systems. Future advancements may focus on optimizing multi-stimuli responsiveness and integrating targeting moieties for enhanced specificity in biomedical applications.