Bioengineering Strategies to Address Key Bottlenecks in Ferroptosis-Based Cancer Therapy: A Critical Review.

More than a decade after ferroptosis was first defined, no agent designed to exploit it has won clinical approval for cancer. We argue that the bottleneck has shifted from mechanism to translation: unsatisfactory pharmacokinetics with unreliable intratumoral accumulation; resistance arising from single-pathway blockade; a scarcity of selective, well-tolerated modulators; and the absence of non-invasive tools for monitoring target engagement. Instead of cataloging nanoplatforms by material class, this critical review organizes bioengineering strategies into four levels of rising functional integration, namely node-specific delivery, multi-pathway combination, stimuli-responsive gating, and theranostic integration, each mapped to one distinct bottleneck. The ordering is ordinal, not evaluative: the most clinically advanced ferroptosis nanomedicine, carbon nanoparticle-iron(II) complex (CNSI-Fe(II)), is a Level 1 platform. Literature was retrieved through systematic searches of PubMed and Web of Science up to June 2026. Synthesizing available preclinical and preliminary clinical findings, this work identifies three cross-cutting translational issues that warrant critical reassessment. Only one ferroptosis nanomedicine has reached human testing; nearly all supporting evidence derives from subcutaneous xenografts in immunodeficient mice, with safety follow-up rarely extending beyond acute timeframes. Passive tumor uptake relying on the enhanced permeability and retention (EPR) effect yields highly variable tumor accumulation that cannot be reliably forecasted for human solid tumors. Non-degradable metallic nanozymes bring unaddressed long-term organ risks originating from systemic metal deposition. Combination treatments administered without companion diagnostic tools fail to filter patient subgroups with treatment sensitivity. We contend that progress now depends less on more elaborate nanocarrier architectures than on predictive large-animal toxicology, 18F-FSPG PET-guided patient stratification ((4S)-4-(3-[18F]fluoropropyl)-L-glutamate positron emission tomography), and locoregional delivery that limits systemic exposure.