  Citation: Chan, M.-H.; Huang, W.-T.; Satpathy, A.; Su, T.-Y.; Hsiao, M.; Liu, R.-S. Progress and Viewpoints of Multifunctional Composite Nanomaterials for Glioblastoma Theranostics. Pharmaceutics 2022, 14, 456. https://doi.org/10.3390/ pharmaceutics14020456 Academic Editors: Magdalena Kusaczuk, Monika Naumowicz and Guillermo Velasco Received: 20 December 2021 Accepted: 16 February 2022 Published: 21 February 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). pharmaceutics Review Progress and Viewpoints of Multifunctional Composite Nanomaterials for Glioblastoma Theranostics Ming-Hsien Chan 1,2 , Wen-Tse Huang 1 , Aishwarya Satpathy 1 , Ting-Yi Su 1 , Michael Hsiao 2,3, * and Ru-Shi Liu 1,2, * 1 Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; ahsien0718@gate.sinica.edu.tw (M.-H.C.); d09223104@ntu.edu.tw (W.-T.H.); d09223109@ntu.edu.tw (A.S.); b06203072@ntu.edu.tw (T.-Y.S.) 2 Genomics Research Center, Academia Sinica, Taipei 115, Taiwan 3 Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan * Correspondence: mhsiao@gate.sinica.edu.tw (M.H.); rsliu@ntu.edu.tw (R.-S.L.) Abstract: The most common malignant tumor of the brain is glioblastoma multiforme (GBM) in adults. Many patients die shortly after diagnosis, and only 6% of patients survive more than 5 years. Moreover, the current average survival of malignant brain tumors is only about 15 months, and the recurrence rate within 2 years is almost 100%. Brain diseases are complicated to treat. The reason for this is that drugs are challenging to deliver to the brain because there is a blood–brain barrier (BBB) protection mechanism in the brain, which only allows water, oxygen, and blood sugar to enter the brain through blood vessels. Other chemicals cannot enter the brain due to their large size or are considered harmful substances. As a result, the efficacy of drugs for treating brain diseases is only about 30%, which cannot satisfy treatment expectations. Therefore, researchers have designed many types of nanoparticles and nanocomposites to fight against the most common malignant tumors in the brain, and they have been successful in animal experiments. This review will discuss the application of various nanocomposites in diagnosing and treating GBM. The topics include (1) the efficient and long-term tracking of brain images (magnetic resonance imaging, MRI, and near-infrared light (NIR)); (2) breaking through BBB for drug delivery; and (3) natural and chemical drugs equipped with nanomaterials. These multifunctional nanoparticles can overcome current difficulties and achieve progressive GBM treatment and diagnosis results. Keywords: glioblastoma; magnetic resonance imaging nanoparticles; near-infrared probes; near- infrared phototherapy; FDA-proved drugs 1. Introduction of Brain Glioblastoma Glioblastoma (GBM) is one of the most common and aggressive brain cancers. The signs and symptoms of glioblastoma are initially nonspecific. Patients may experience headaches, personality changes, nausea, and stroke-like symptoms. The symptoms usually worsen quickly and may develop into unconsciousness [1]. The diagnosis of glioblastoma is usually comprehensively judged by computer tomography, MRI, and biopsy. The treatment of GBM is generally chemotherapy and radiation therapy after surgery [2]. Temozolomide (TMZ) drugs are often used as chemotherapy for glioblastoma [3]. High-dose steroids can be used to help reduce swelling and symptoms. It is unclear whether trying to eradicate the tumor or removing most of the cancer is more helpful to the patient [4]. Glioblastoma usually recurs under complete treatment. After diagnosis, the typical survival period is 12–15 months, and less than 3–7% of people survive for more than five years. Without treatment, the survival period is usually only 3 months, which shows that GBM is a very deadly cancer. GBM is difficult to treat because the brain tissue is intertwined under the blood–brain barrier (BBB), composed of endothelial cells, astrocytes, and the basement membrane [5]. This “barrier” can selectively prevent certain substances from being removed Pharmaceutics 2022, 14, 456. https://doi.org/10.3390/pharmaceutics14020456 https://www.mdpi.com/journal/pharmaceutics