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In this Account, we summarize our systematic efforts to address these challenges through two complementary strategies: 1) functionalization of Pt(IV) prodrugs and 2) spatially controlled targeted delivery. The kinetic inertness and octahedral geometry of Pt(IV) complexes offer a versatile platform for axial functionalization, allowing the integration of diverse bioactive ligands that are released upon intracellular reduction. Exploiting this feature, we have developed multifunctional Pt(IV) prodrugs that co-target DNA damage repair and apoptotic pathways, rewire cholesterol and energy metabolism, induce nonapoptotic cell death including PANoptosis and autophagy-associated death, and epigenetically silence resistance-associated gene networks via chromatin compaction. To engage the tumor immune microenvironment, we have incorporated immunomodulators\u2500including STING agonists, TREM2\/CD33 inhibitors, and STAT3 blockers\u2500to amplify innate and adaptive antitumor immunity. Furthermore, we have developed radiotherapy-responsive Pt(IV) prodrugs that undergo rapid, X-ray-triggered reduction mediated by hydrated electrons, enabling spatiotemporally precise drug activation with markedly attenuated systemic toxicity. This strategy is currently advancing toward clinical translation through IND-enabling studies. In parallel, we have established targeted delivery platforms to improve the spatial precision of Pt agents. Mitochondria-targeted complexes redirect cytotoxicity to an organelle lacking efficient DNA repair, disrupting bioenergetics and triggering intrinsic apoptosis. At the tissue level, biotin-mediated targeting exploits overexpressed vitamin transporters for tumor-selective accumulation, while Pt(IV)\u2013antibody conjugates (Pt-ADCs) achieve antigen-specific delivery, upregulate tumor MHC-I expression, expand TCR clonotypes, and synergize with PD-1 blockade. Additionally, a stimuli-responsive in situ self-assembly strategy enables enzyme-triggered nanostructure formation and intracellular disassembly for enhanced tumor accumulation and burst drug release. An immunocompetent patient-derived organoid platform has been established to screen these agents in a clinically relevant setting. The integration of multifunctional modulation, targeted delivery, and externally controlled activation within single Pt-based systems creates a synergistic framework that simultaneously addresses resistance and toxicity. Moving forward, our research will focus on optimizing pharmaceutical properties, advancing radiotherapy-responsive Pt(IV) prodrugs and Pt-ADCs toward clinical evaluation, and refining predictive screening platforms. These programmable Pt therapeutics hold considerable promise for delivering safer and more effective precision chemotherapy to cancer patients.<\/jats:p>","DOI":"10.1021\/acs.accounts.6c00342","type":"journal-article","created":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T13:00:44Z","timestamp":1783774844000},"page":"2438-2449","source":"Crossref","is-referenced-by-count":1,"title":["Addressing\nClinical Challenges of Platinum Anticancer\nDrugs through Rational Chemical Design"],"prefix":"10.1021","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9833-7423","authenticated-orcid":true,"given":"Shuren","family":"Zhang","sequence":"first","affiliation":[{"name":"Nanjing University , , ,","place":["Nanjing, China, 210023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4986-9308","authenticated-orcid":true,"given":"Zijian","family":"Guo","sequence":"additional","affiliation":[{"name":"Nanjing University , , ,","place":["Nanjing, China, 210023"]},{"name":"Nanchuang (Jiangsu) Institute of Chemistry and Health , ,","place":["Nanjing, China, 211899"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,11]]},"reference":[{"key":"2026080408064413200_cit1","doi-asserted-by":"publisher","first-page":"e202309043","DOI":"10.1002\/anie.202309043","article-title":"Overcoming Cancer Resistance to Platinum Drugs by Inhibiting\nCholesterol Metabolism","volume":"62","author":"Wang","year":"2023","journal-title":"Angew. 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