Multifunctional platinum(IV) prodrugs: Targeted delivery, stimuli-responsive release, and precision oncology

Platinum-based chemotherapy remains the cornerstone of cancer treatment, but it faces inherent limitations such as dose-limiting toxicity, acquired resistance, and poor tumor specificity. Platinum(IV) prodrugs, with their octahedral configuration and two modifiable axial sites, have evolved into multifunctional platforms that integrate targeted delivery, stimulus-responsive activation, and combination therapy. This review systematically summarizes the latest advances in platinum(IV) prodrug delivery strategies, including: (i) molecule-recognition-driven targeting (e.g., folate receptor, integrin αvβ3, PSMA, and mitochondrial targeting); (ii) carrier-mediated smart systems (inorganic/organic nanocarriers and biomimetic platforms); and (iii) endogenous/exogenous stimulus-responsive release. It also highlights recent advances in the use of platinum(IV) prodrugs in combined chemotherapy-immunotherapy, as well as their chemical mechanisms for overcoming platinum resistance, such as circumventing CTR1/ATP7A transport defects, inhibiting GST/GSH detoxification, and blocking DNA damage repair. This review integrates molecular activation chemistry, delivery engineering, and drug resistance regulation to reveal the intrinsic constraints between platinum(IV) molecular structures and delivery systems. The article evaluates key barriers to clinical translation, including clinical insights from cisplatin, intratumoral reduction heterogeneity, cross-resistance with platinum(II) drugs, and the lack of predictive biomarkers. It further proposes a biomarker-guided framework for patient stratification based on tumor receptor expression, redox status, and DNA damage repair characteristics, matching specific molecular phenotypes with corresponding Pt(IV) prodrug designs and delivery strategies. This review aims to provide guidance for the development of a new generation of platinum(IV) anticancer drugs in the field of precision oncology.