Natural Microgels Overcome Nanoparticle Retention Barriers for Hyperthermia and Tumor Regression

ABSTRACT Clinical translation of nanoparticle (NP) based hyperthermia has long been constrained by poor tumor retention and rapid systemic clearance, resulting in transient and subtherapeutic heating. Here, we present a biodegradable, bioinspired carrier system derived from sunflower pollen microgels (PMs) that overcomes these limitations through geometry‐guided retention and tumor‐microenvironment‐responsive degradation. The spiky exine architecture of PMs, mimicking the adhesive morphology of natural pollen, enables mechanical interlocking within tumor tissue, while cationic liposome coating facilitates electrostatic assembly of Fe 3 O 4 NPs. The resulting PM/Lipo/NP composites achieve stable, homogeneous heating at therapeutic temperatures (44.9°C ± 0.3°C) under alternating magnetic fields for up to 21 days far exceeding the performance of free Fe 3 O 4 NPs (39.6°C ± 0.4°C). In vivo, this prolonged retention drives near‐complete tumor regression with no detectable systemic toxicity, and the pollen matrix gradually degrades under tumor‐relevant oxidative conditions (H 2 O 2 , pH 6.5). This study presents a structure‐driven delivery concept, showing that bioinspired microgels can function as biodegradable, shape‐anchored platforms for sustained magnetic hyperthermia and effective local cancer therapy.