Light-Triggered Drug Delivery System

• Light-triggered drug delivery systems are platforms that use incident light (visible, UV, or NIR) to activate photoresponsive materials for spatiotemporal control of drug release.
• They integrate diverse nanostructured architectures—such as TiO₂ nanotubes, polymer microcapsules, carbon nitride microswimmers, and COF microrobots—to achieve mechanisms like photocatalytic bond scission and photothermal rupture.
• Recent studies demonstrate precise navigation, real-time imaging, and effective therapeutic outcomes, highlighting innovations in biocompatibility and controlled release kinetics.

Light-triggered drug delivery systems utilize tailored photochemistry, photothermal effects, and photoresponsive materials to achieve spatiotemporal control over pharmaceutical release within biological environments. These platforms harness incident electromagnetic radiation—typically visible, UV, or near-infrared light—either to initiate local bond scission, induce heating, drive propulsive cargo carriers, or modulate the permeability of nano- and microcontainers loaded with therapeutics. Recent research has yielded diverse architectures including TiO₂ nanotube arrays, polymer microcapsules modified by resonant nanoparticles, carbon nitride-based microswimmers, covalent organic framework microrobots, and MRI-navigated capsule robots with ultrasonic actuation, each designed to address the challenges of delivery precision, biocompatibility, and practical stimulatory control.

1. Photochemical and Photothermal Initiation Mechanisms

Visible-light or laser irradiation is used to trigger drug release via at least two principal mechanisms: photocatalytic bond scission and photothermal capsule rupture.

• Photocatalytic Scission: TiO₂ nanotube arrays functionalized with Au nanoparticles exploit localized surface plasmon resonance (SPR) under visible light (λ > 420 nm). SPR-mediated electron transfer to the TiO₂ conduction band initiates photocatalytic cleavage of long hydrophobic chains (ODPA, dodecanethiol), uncapping the nanotube entrances and allowing drug egress. Simultaneously, reactive oxygen species (O₂•–, H₂O₂) generated by photocatalysis can break silane linkers (GPMS) anchoring drug molecules on the inner walls, resulting in further controlled release (Xu et al., 2016).
• Photothermal Rupture: Polymer capsules embedded with α-Fe₂O₃ nanoparticles (NPs) convert incident laser energy (e.g., 790 nm NIR) to heat via excitation of Mie resonances, quantified by

$$\delta T_{np} = \frac{I \cdot \sigma_{abs}}{4\pi \kappa_2 R},$$

where $I$ is intensity, $\sigma_{abs}$ absorption cross-section, $\kappa_2$ medium thermal conductivity, $R$ NP radius. Capsule wall temperature rises to ∼170°C, deforming or rupturing the polymer shell and thus releasing encapsulated therapeutic agents (Zograf et al., 2019).

Photoresponsive molecular charge storage and optoionic effects in poly(heptazine imide) (PHI) carbon nitride drive light-induced drug expulsion and propulsion. Photoexcitation locally alters ion gradients and zeta potential, expelling cargo, especially under hypoxic conditions (Sridhar et al., 2021).

2. Nanostructured Architectures and Material Design

Light-triggered delivery relies on sophisticated architectures integrating responsive materials atop or within drug-laden nanostructures.

• Double-Layered TiO₂ Nanotubes (Xu et al., 2016): Upper hydrophobic layer (ODPA + AuNPs + NDM) acts as a visible-light-removable cap, lower hydrophilic layer (GPMS silane functionalization) stores drugs, facilitating spatial separation of storage and release functionality.
• Polymer Microcapsules with Dielectric Nanoparticles (Zograf et al., 2019): α-Fe₂O₃ NPs embedded in walls provide broad spectral absorption and efficient heating; interior cavity loaded with therapeutics.
• PHI Carbon Nitride Microswimmers (Sridhar et al., 2021): Dual porosity (textural and structural, pore radii ~3.84 Å), abundant surface amine groups permit high (185% mass) loading of doxorubicin via physisorption and electrostatic interactions; suppression of passive release observed for ≥30 days.
• Covalent Organic Framework (COF) Microrobots (Sridhar et al., 2023):
  • TABP-PDA-COF: Spherical sub-micron particles, 3.4 nm pores, 685 m²/g surface area.
  • TpAzo-COF: Irregular, micron-sized spongelike aggregates, 2.6 nm pores.
  • High drug and dye loading, including chemotherapeutics, peptides, and imaging agents (e.g., indocyanine green).

3. Drug Loading, Triggering, and Kinetic Modulation

Drug loading processes exploit high internal surface area and specific chemical reactivity:

• Covalent Attachment: Epoxy groups of GPMS (silane) in TiO₂ arrays form stable linkages to antibiotics (e.g., AMP), almost eliminating premature release (Xu et al., 2016).
• Physisorption and Electrostatic Binding: PHI and COF platforms load cargo by soaking in drug solutions, exploiting porous networks and zeta potential differences for high uptake efficiencies (Sridhar et al., 2021, Sridhar et al., 2023).
• Microcontainer Encapsulation: VCR loaded into polymer microcapsules is retained until photothermal rupture (Zograf et al., 2019).

Release kinetics are controlled by:

• Light Exposure Parameters: Release rate and efficiency ($n = \frac{m_x}{m_0 - m_r} \times 100\%$, $m_0$ initial load, $m_r$ residual drug, $m_x$ released amount) can be tuned by varying irradiation intensity, wavelength (visible/NIR), and illumination time (Xu et al., 2016, Zograf et al., 2019).
• Environmental Triggers: COF microrobots feature decoupled propulsion/release; motion navigated by light, but acidification (pH decrease) triggers rapid drug desorption at the target (Sridhar et al., 2023).

4. Propulsion and Navigation in Biological Media

Responsive propulsion strategies extend targeted delivery capabilities:

• PHI Carbon Nitride Microswimmers: High-speed locomotion (15–23 μm/s) is achieved in multi-ionic solutions (up to 1 M) and biological fluids without dedicated fuels, attributed to optoionic charge gradients and dual-porosity design countering Debye length collapse (Sridhar et al., 2021). The classical Helmholtz–Smoluchowski formula ($U = \mu E$) is insufficient for characterizing motion in porous microswimmers, which instead display ionic transport through their structure.
• COF Microrobots: Phototactic control of TABP-PDA-COF (maximum at 470 nm, up to 16.4 μm/s) and TpAzo-COF (significant motion at 560–630 nm) allows traversal of intraocular fluids; design tailored for navigation in vitreous mesh and deep biological tissues (Sridhar et al., 2023).
• MRI-Actuated Capsule Robots: Capsules containing magnetic cores are maneuvered via gradient-derived forces ($F_m = m_s \cdot G$) within MRI scanners, achieving navigation speeds up to 1.13 cm/s in ex vivo intestine. Precise localization and remote control are enhanced by high-resolution MR feedback (Tiryaki et al., 2023).

5. Antibacterial and Therapeutic Efficacy

Efficacy in vitro and ex vivo has been rigorously assessed for antibacterial and anticancer activities.

• TiO₂-AuNP Arrays: Upon visible-light activation, AMP release yields pronounced drops in E. coli colony formation. Control groups (bare TiO₂, AuNP-TiO₂ without drug) exhibit weak bactericidal effects (Xu et al., 2016).
• Polymer Capsules with α-Fe₂O₃: NIR-triggered VCR release induces significant viability reduction in carcinoma cells, with stem cells displaying higher resistance. Uptake and localization confirmed by confocal microscopy; phototoxic threshold not reached at operational laser intensities (Zograf et al., 2019).
• PHI and COF Systems: Biocompatibility established across multiple cell lines with negligible cytotoxicity. Hypoxia-enhanced DOX release recorded for PHI microswimmers, suggesting strong applicability for oxygen-deprived tumor environments (Sridhar et al., 2021, Sridhar et al., 2023).

6. Imaging, Visualization, and Theranostic Integration

Integration with advanced imaging modalities and tracing agents permits real-time tracking and theranostic application.

• Photoacoustic Imaging and OCT: COF carriers loaded with indocyanine green (ICG) exhibit strong NIR absorption, enabling both photoacoustic signal enhancement and OCT-based trajectory monitoring in intraocular fluid (Sridhar et al., 2023).
• Raman Nanothermometry: α-Fe₂O₃ NPs provide multi-peaked Raman spectra, allowing detailed local temperature monitoring (resolution ~40 K at capsule wall) during photothermal actuation (Zograf et al., 2019).
• MRI and HIFU Synergy: Capsule robots monitored and actuated noninvasively and precisely via MRI imaging combined with HIFU-controlled release based on acoustic streaming and bubble removal (Tiryaki et al., 2023).

7. Limitations, Technical Challenges, and Future Directions

Current systems face multiple technical hurdles before clinical adoption:

• Penetration Depth: Use of visible/UV light is constrained by limited tissue penetration; NIR activation (∼790 nm) is preferred for deep-tissue delivery (Zograf et al., 2019, Sridhar et al., 2023).
• Release Control and Reproducibility: For containers relying on thin hydrophobic caps or air bubble stoppers (in HIFU/MRI robots), precise control of cap integrity and activation force balance is required. Capsule size scaling, material stability under fabrication, and avoidance of image artifacts limit implementation (Xu et al., 2016, Tiryaki et al., 2023).
• Biocompatibility and Clearance: Long-term tissue compatibility, nanoparticle degradation, and delivery byproducts require comprehensive in vivo paper (Zograf et al., 2019, Sridhar et al., 2021).
• Active Navigation vs. Release Decoupling: COF microrobots dissociate propulsion (light) from payload release (pH change), presenting both flexibility and complexity for triggered therapies (Sridhar et al., 2023).
• Environmental Adaptability: High ion tolerance in PHI and COF microdevices suggests wider applicability, but the effect of ionic strength on photocatalytic activity and carrier stability needs further exploration (Sridhar et al., 2021, Sridhar et al., 2023).

Future developments center on extending light-triggered delivery to NIR-responsive systems, refining propulsion/release decoupling, integrating multimodal imaging and sensing, and scaling fabrication while maintaining reproducibility and environmental adaptability.

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Light-triggered drug delivery platforms continue to evolve across modalities and architectures, integrating advanced nanophotonic, optoionic, and microfabrication principles for precise, minimally invasive, and multifunctional pharmaceutical administration. This field bridges photochemistry, nanomaterials engineering, robotics, and biomedical imaging, reflecting a convergence of technical innovation with therapeutic promise (Xu et al., 2016, Zograf et al., 2019, Sridhar et al., 2021, Sridhar et al., 2023, Tiryaki et al., 2023).