Beyond chemotherapy: Spatiotemporal activation of metal complexes for deep-tissues precision medicine

Metal-based complexes have emerged as powerful agents in anticancer therapy, demonstrating exceptional activity and positioning themselves as highly promising candidates in the field. Among these, platinum-based antitumor drugs are extensively employed in current chemotherapy protocols. However, their clinical utility is significantly constrained by challenges such as drug resistance, non-specific biodistribution, and irreversible toxicities. Recent advances underscore that precise spatiotemporal activation of metal-based drugs through external radiation offers a novel mechanism of action distinct from conventional chemotherapy. This approach enhances therapeutic efficacy while simultaneously mitigating side effects and cross-resistance, addressing pivotal limitations inherent to traditional metal-based therapeutics. External stimuli, including near-infrared (NIR) light, ultrasound (US), and X-rays, possess superior tissue penetration compared to ultraviolet-visible light, rendering them particularly advantageous for targeting deep-seated tumors. Within this framework, we comprehensively review recent developments in the activation of metal-based drugs via NIR light, US, and X-rays, with a focus on molecular metal complexes, supramolecular coordination complexes, and metal-organic frameworks. Critical aspects covered include their design principles, photophysical and photochemical properties, and biomedical applications. Finally, we address the difficulties and future directions for the biomedical field and clinical translation of these metal complexes.