The Dual Role of Protein Corona in Tumor Targeting, Immunotherapy, and Diagnosis

(i) In vivo circulation: If the main components of the formed protein corona are opsonins, such as coagulation proteins, complement, immunoglobulins, and fibrin, it can lead to the recognition and clearance of nanoparticles by the mononuclear phagocyte system; if the main components of the protein corona are dysopsonins, such as apolipoproteins and albumin, it can allow nanoparticles to evade the surveillance of the mononuclear phagocyte system, achieving a longer in vivo circulation time.

(ii) Accumulation at the tumor site: The formation of the protein corona leads to an increase in nanoparticle size, making it difficult for them to extravasate from blood vessels to the tumor site; or after crossing the blood vessels, they may not easily return, which is more favorable for accumulation at the tumor site.

(iii) Penetration of tumor tissue: The formation of the protein corona increases the size of nanoparticles, reducing their penetration capability in tumor tissues (e.g., the binding of poly(lactic-co-glycolic acid) nanoparticles with extracellular matrix proteins alters their size and leads to a decrease in penetration capability [6]); however, the mechanism by which the protein corona enhances nanoparticle penetration still requires further study.

(iv) Uptake by tumor cells: The protein corona can cover modified ligands on the nanoparticle surface or exhibit unfavorable steric effects, thereby reducing the interaction between nanoparticles and cell membranes, leading to decreased uptake; on the other hand, specific proteins in the protein corona can also cause specific pathways of cellular internalization by recognizing receptors on tumor cell membranes (e.g., apolipoprotein E in the protein corona can recognize low-density lipoprotein receptors highly expressed on Hep G2 tumor cells, resulting in increased nanoparticle uptake [7]).

Based on this, to improve the tumor targeting efficiency of nanoparticles, one can address the dual impact of protein corona. On one hand, by using PEG modification, zwitterionic coatings (such as sulfonated trimethyl ammonium ethyl ester and poly(methacrylic acid) phosphatidylcholine), and biological membrane coatings to encapsulate nanoparticles, the formation of protein corona can be weakened; on the other hand, nanoparticles can be modified to adsorb specific proteins in vivo (e.g., modifications of polyphosphate favor the adsorption of apolipoprotein A-I and apolipoprotein J [8]) or pre-encapsulated with specific proteins in vitro (such as albumin, transferrin, and lactoferrin) to form an artificial protein corona, enhancing their tumor targeting efficiency.

1. 3. The Impact and Application of Protein Corona Formation on Tumor Immunotherapy

Tumor immunotherapy refers to the treatment methods that utilize immunological principles and methods to activate immune cells in the body and enhance the body’s anti-tumor immune response to control and eliminate tumors. The formation of protein corona has a bidirectional impact on the anti-tumor immunotherapy of nanoparticles.

First, the protein corona on the surface of nanoparticles can exert an immune blinding effect, covering part or all of the molecules or antigens on the surface of nanoparticles, thereby inhibiting their interaction with specific receptors and affecting the expected outcomes; on the other hand, specific proteins in the protein corona can serve as specific ligands for receptors on immune cell surfaces, enhancing the immunogenicity of nanoparticles and triggering immune responses. Based on this, the potential applications of protein corona in anti-tumor immunotherapy have been widely explored, such as pre-encapsulating complement protein 1q on the nanoparticle surface, which can effectively enhance cellular uptake of nanoparticles and increase the release of pro-inflammatory cytokines, creating an effective anti-tumor positive feedback loop in vivo [9].

Figure 4. The effect of protein corona on the interaction between nanoparticles and the mononuclear macrophage system in immunotherapy.

1. 4. Protein Corona as a New Type of Biomarker for Tumor Diagnosis

Different types of tumors have been shown to express different specific proteins, leading to changes in the concentrations of corresponding proteins in plasma, which results in differences between plasma derived from tumor patients and healthy volunteers [10]. When nanoparticles are incubated in plasma samples from tumor patients, specific proteins in the plasma will be adsorbed and concentrated on the surface of nanoparticles, forming a cancer protein corona. Therefore, by detecting the protein corona formed on the surface of nanoparticles, changes in the composition and concentration of proteins in plasma caused by tumor growth and invasion can be identified, enabling early detection of tumors.

However, the composition of the protein corona can also be influenced by other diseases in patients, which may interfere with the accuracy of tumor diagnosis results; meanwhile, there is still a significant lack of protein corona databases for different tumor types based on the same nanoparticle diagnostic platform, thus the application value of protein corona as a biomarker for tumor diagnosis still needs further exploration.

Figure 5. Protein corona can serve as a new type of biomarker for tumor diagnosis.

5. Summary and Outlook

After nanoparticles enter the biological body, the protein corona formed on their surface will affect their fate in vivo and produce a dual effect like the “Janus” in tumor targeting, tumor immunotherapy, and tumor diagnosis. It is important to note that the composition of the protein corona has species differences, therefore, it is encouraged to use appropriate human-derived cells or blood samples for protein corona research, which will help accurately understand the impact or application of protein corona on nanoparticles in the human body, thereby narrowing the gap between preclinical research and clinical trials. At the same time, the protein corona will also affect the clinical translation of nanoparticles in tumor detection and treatment, thus it is necessary to re-evaluate the impact of protein corona formation on the efficacy and safety of already approved clinical nanomedicines..