Background/Objectives: In heart failure (HF) with reduced ejection fraction (HFrEF), the early diagnosis and proper treatment of comorbidities (CMs) are of fundamental relevance. Our aim was to assess the prevalence of CMs among real-world patients requiring hospitalisation for HFrEF and to investigate the effect of CMs on the implementation of guideline-directed medical therapy (GDMT) and on all-cause mortality (ACM). Methods: The data of a consecutive HFrEF patient cohort hospitalised for HF between 2021 and 2024 were analysed retrospectively. Sixteen CMs (6 CV and 10 non-CV) were considered. Patients were divided into three categories: 0–3 vs. 4–6 vs. ≥7 CMs. GDMT at discharge and ACM were compared among CM categories. The predictors of 1-year ACM were also evaluated. Results: From the 388 patients (male: 76%, age: 61 [50–70] years; NT-proBNP: 5286 [2570–9923] pg/mL; ≥2 cardiovascular–kidney–metabolic disease overlap: 46%), a large proportion received GDMT (RASi: 91%; βB: 85%; MRA: 95%; SGLT2i: 59%; triple therapy [TT: RASi+βB+MRA]: 82%; quadruple therapy [QT: TT + SGLT2i]: 54%) at discharge. Multimorbidity was accompanied with a (p < 0.05) lower application ratio of RASi (96% vs. 92% vs. 85%; 0–3 vs. 4–6 vs. ≥7 CMs) and βB therapy (94% vs. 85% vs. 78%), while MRA (99% vs. 94% vs. 94%) and SGTL2i use (61% vs. 59% vs. 57%) did not differ (p > 0.05). Patients with multimorbidity were less likely to be treated with TT (93% vs. 82% vs. 73%, p = 0.001), while no difference was detected in the implementation of QT (56% vs. 54% vs. 50%, p = 0.685). The 1-year ACM of patients with an increased burden of CMs was higher (9% vs. 13% vs. 25%, p = 0.003). The risk of 1-year ACM was favourably affected by the use of TT/QT and less severe left ventricular systolic dysfunction, while having ≥5 CMs had an unfavourable impact on prognosis. Conclusions: According to our real-world analysis, HFrEF patients with an increased burden of CMs can expect a less favourable outcome. However, modern GDMT can even be applied in this patient population, resulting in a significantly improved prognosis. Thus, clinicians should insist on the early, conscious implementation of a prognosis-modifying drug regime in multimorbid HF patients as well.

Cell delivery of therapeutic macromolecules and nanoparticles is a critical drug development challenge. Translocation through lipid raft-mediated endocytic mechanisms is being sought, as it can avoid rapid lysosomal degradation. Here, we present a set of short α/β-peptide tags with high affinity to the lipid raft-associated ganglioside GM1. These sequences induce effective internalization of the attached immunoglobulin cargo. The structural requirements of the GM1-peptide interaction are presented, and the importance of the membrane components are shown. The results contribute to the development of a receptor-based cell delivery platform.