A narrative review of emerging chemoprotective agents for chemotherapy-induced toxicity: nanoformulated natural products, dual COX-2/TNF-α inhibitors, and Nrf2 modulators.

Background: Chemotherapy-induced toxicity remains a major cause of treatment discontinuation, reduced quality of life, and long-term morbidity in cancer survivors. Established chemoprotective agents (dexrazoxane, mesna, and amifostine) are limited by narrow indications (dexrazoxane: only anthracycline cardiotoxicity), significant adverse effects (amifostine: hypotension in 62%), and lack of efficacy against common toxicities such as peripheral neuropathy. Objective: This focused review evaluates emerging chemoprotective strategies with preclinical or early clinical data published between 2015 and 2025, with an emphasis on agents that address unmet clinical needs. Methods: This is a critical narrative review, not a systematic review. A literature search was conducted in PubMed, Scopus, and ClinicalTrials.gov (2015-2025) using keywords including "chemoprotection," "nanoparticle," "curcumin," "resveratrol," "dual COX-2/TNF-α inhibitor," "Nrf2 modulator," and "chemotherapy-induced peripheral neuropathy." Articles were selected based on relevance to chemoprotection, mechanistic clarity, and availability of preclinical or clinical data. Results: Three major emerging categories were identified: (i) Nanoformulated natural products such as curcumin, resveratrol, luteolin, and naringenin encapsulated in polymeric, lipid, or cyclodextrin-based nanocarriers, demonstrate improved bioavailability and enhanced efficacy in preclinical models though chemoprotection-specific clinical data remain limited (ii) Dual COX-2/TNF-α inhibitors (e.g., NO-donating aspirin). simultaneously suppress inflammatory and oncogenic signaling (NF-κB, β-catenin, STAT3) and have shown polyp burden reduction in familial adenomatous polyposis, though cardiovascular safety concerns persist. (iii) Nrf2 pathway modulators, including sulforaphane (activator) and brusatol (inhibitor), present a paradox: activation protects normal tissues but may also shield tumors. Physical strategies (limb hypothermia) and repurposed drugs (metformin) offer additional avenues but need Phase III validation. Emerging mechanistic frontiers including ferroptosis inhibition, pyroptosis modulation, and neuroimmune targeting represent additional promising directions. Conclusion: Nanoformulation is the most technologically mature strategy for overcoming bioavailability barriers. Dual inhibitors offer pleiotropic benefits but require safer designs. Nrf2 modulators demand careful patient stratification. Future trials must incorporate biomarker-driven enrollment and standardized chemoprotection endpoints. Comparative analysis across categories reveals that strategies with simpler mechanisms and well-defined surrogate endpoints have advanced furthest clinically, highlighting the importance of rigorous trial design and validated biomarkers for successful translation.