The integration of porous covalent organic frameworks (COFs) with fluorophores or paramagnetic metals represents a significant advancement in theranostic nanoplatforms. These materials combine structural stability, tunable porosity, and functional versatility, enabling simultaneous drug delivery and imaging. The π-conjugated backbones of COFs provide exceptional stability, while their pore sizes can be precisely tailored to accommodate diverse therapeutic payloads. Additionally, two-photon excitation offers unique advantages for deep-tissue imaging with minimal photodamage, making these systems highly promising for biomedical applications.

The structural integrity of COFs arises from their π-conjugated backbones, which are formed through strong covalent bonds such as boronate esters, imines, or triazines. These linkages ensure chemical and thermal stability, allowing COFs to maintain their porosity and functionality under physiological conditions. The extended π-conjugation also facilitates charge transfer, which is crucial for integrating fluorophores or paramagnetic metals. For example, incorporating tetraphenylethene-based fluorophores into the COF backbone enhances fluorescence emission due to aggregation-induced emission effects, while paramagnetic metals like gadolinium or manganese enable magnetic resonance imaging (MRI) contrast. The robustness of these frameworks ensures that the integrated imaging agents remain stable during drug loading and release.

Pore size customization is a critical feature of COFs, as it directly influences their drug-loading capacity and selectivity. By varying the building blocks and linkage chemistry, pore diameters can be tuned from microporous (less than 2 nm) to mesoporous (2–50 nm) scales. Larger pores are suitable for loading bulky therapeutic agents such as proteins or nucleic acids, while smaller pores optimize the encapsulation of small-molecule drugs like doxorubicin or paclitaxel. The uniformity of these pores ensures consistent drug release kinetics, which can be further modulated by surface functionalization with stimuli-responsive groups. For instance, pH-sensitive groups enable controlled release in acidic tumor microenvironments, while redox-active linkers respond to intracellular glutathione levels.

The incorporation of fluorophores into COFs enables real-time tracking of drug delivery and biodistribution. Two-photon excitation is particularly advantageous for in vivo imaging due to its deeper tissue penetration and reduced autofluorescence compared to single-photon methods. Fluorophores with large two-photon absorption cross-sections, such as diketopyrrolopyrrole or porphyrin derivatives, can be covalently linked to the COF backbone, providing bright and photostable signals. This allows for high-resolution imaging of drug accumulation at target sites, facilitating precise monitoring of therapeutic efficacy. Moreover, the porous structure of COFs prevents fluorophore aggregation, which often quenches fluorescence in conventional nanoparticle systems.

Paramagnetic metals integrated into COFs enhance their utility as MRI contrast agents. Gadolinium(III) complexes, for example, can be coordinatively bound to the COF’s Lewis basic sites, such as imine or triazine groups, ensuring high relaxivity for improved imaging sensitivity. The porous framework prevents metal leaching, a common issue with small-molecule contrast agents, thereby reducing toxicity risks. Additionally, the combination of MRI and fluorescence imaging in a single COF platform enables multimodal diagnostics, offering complementary spatial and temporal resolution for comprehensive disease assessment.

The dual functionality of these COFs extends to their drug-loading mechanisms. Hydrophobic drugs can be adsorbed within the porous network via π-π stacking or van der Waals interactions, while hydrophilic drugs may be encapsulated through hydrogen bonding or electrostatic interactions. The high surface area of COFs, often exceeding 1000 m²/g, allows for substantial drug payloads without compromising structural integrity. Controlled release is achieved by leveraging the dynamic nature of COF linkages, which can respond to external stimuli such as light, temperature, or enzymatic activity. For example, UV light can cleave photolabile bonds in the COF backbone, triggering rapid drug release at precise locations.

The biocompatibility of COFs is another key consideration for their clinical translation. Surface modification with polyethylene glycol (PEG) or zwitterionic polymers reduces opsonization and prolongs circulation time, enhancing passive targeting to tumors via the enhanced permeability and retention effect. Biodegradable COFs, constructed from enzymatically cleavable linkers, offer an additional safety advantage by ensuring gradual breakdown and clearance after fulfilling their therapeutic function.

In summary, porous COFs structurally integrated with fluorophores or paramagnetic metals represent a versatile platform for theranostic applications. Their π-conjugated backbones provide exceptional stability, while tunable pore sizes accommodate diverse drug payloads. Two-photon excitation and multimodal imaging capabilities enable precise tracking of drug delivery, with minimal photodamage and high spatial resolution. The combination of high drug-loading capacity, stimuli-responsive release, and biocompatibility positions these materials at the forefront of nanomedicine innovation. Future research should focus on optimizing synthesis scalability and conducting comprehensive in vivo evaluations to accelerate their clinical adoption.