Shielding Ferritin with a Biomineralized Shell Enables Efficient Modulation of Tumor Microenvironment and Targeted Delivery of Diverse Therapeutic Agents

Abstract

Ferritin (Fn) is considered a promising carrier for targeted delivery to tumors, but the successful application in vivo has not been fully achieved yet. Herein, strong evidence is provided that the Fn receptor is expressed in liver tissues, resulting in an intercept effect in regards to tumor delivery. Building on these observations, a biomineralization technology is rationally designed to shield Fn using a calcium phosphate (CaP) shell, which can improve the delivery performance by reducing Fn interception in the liver while re‐exposing it in acidic tumors. Moreover, the selective dissolution of the CaP shell not only neutralizes the acidic microenvironment but also induces the intratumoral immunomodulation and calcification. Upon multiple cell line and patient‐derived xenografts, it is demonstrated that the elaboration of the highly flexible Fn@CaP chassis by loading a chemotherapeutic drug into the Fn cavity confers potent antitumor effects, and additionally encapsulating a photosensitizer into the outer shell enables a combined chemo‐photothermal therapy for complete suppression of advanced tumors. Altogether, these results support Fn@CaP as a new nanoplatform for efficient modulation of the tumor microenvironment and targeted delivery of diverse therapeutic agents.

Novel Bioengineering Strategies to Improve Bioavailability and In Vivo Circulation of H-Ferritin Nanocages by Surface Functionalization

“…It is known that the high expression of TfR1 in the liver may interfere with HFn accumulation in tumors. Indeed, it has been observed that a co-culture with liver cells may cause reduced uptake efficiency by tumor cells, thus negatively affecting HFn’s delivery to the tumor . To overcome this limitation, a biomineralization strategy of shielding HFn with a calcium phosphate (CaP) shell has been proposed.…”

“…Indeed, it has been observed that a co-culture with liver cells may cause reduced uptake efficiency by tumor cells, thus negatively affecting HFn’s delivery to the tumor. 23 To overcome this limitation, a biomineralization strategy of shielding HFn with a calcium phosphate (CaP) shell has been proposed. Indeed, the presence of a mineral-reinforced coating is expected to enhance HFn’s serum stability, as likewise observed for CaP-mineralized micelles.…”

“…Ultimately, extensive evaluations performed on multiple cell lines and patient-derived xenograft models supported the relevance of this nanoplatforms as an efficient nanostrategy for promoting tumor targeting and accumulation ( Figure 2 ). 23 …”

Connecting Calcium-Based Nanomaterials and Cancer: From Diagnosis to Therapy

“…e TEM images of Fn and Fn@CaP. f Elemental mapping analysis (left panel) and energy dispersive spectroscopy (EDS) analysis (right panel) of Fn@CaP [ 70 ]. Copyright 2022, Wiley–VCH …”

“…For example, Wang and co-workers coated ferritin (Fn) with CaP to enclose Fn within a “temporary protective shell” by biomineralization technology to increase the enrichment of Fn in the target region, and the TME-responsive dissolution of CaP shell can not only neutralize tumor acidity but also induce intratumor immune regulation and tumor calcification (Fig. 4 d–f) [ 70 ]. Due to its well-behaved biocompatibility, biodegradability, and controlled release behavior, CaP nanoplatform provides a profound paradigm for effective cancer therapy and has great potential for in clinical transformation.…”